N-aryl-n-(1-alkyl-4-piperidinyl)-arylacetamides

ABSTRACT

Novel N-aryl-N-(1-L-4-piperidinyl)arylacetamides useful as antiarrhythmic agents, a method of treating arrhythmia which comprises the systemic administration of such compounds to warm-blooded animals and pharmaceutical compositions to be used therefor.

CROSS-REFERENCE TO RELATED APPLICATIONS

This is a continuation-in-part of our copending application Ser. No.713,756, filed Aug. 12, 1976, now abandoned, which in turn is acontinuation-in-part of our parent application Ser. No. 615,131, filedSept. 23, 1975, now abandoned; and our divisional applications thereof:Ser. Nos. 700,351, 700,352, 700,635, 700,636, 700,637, 700,638 and700,694, all filed June 28, 1976 and all now abandoned.

BACKGROUND OF THE INVENTION

This invention pertains to the field ofN-aryl-N-(4-piperidinyl)-arylacetamides. In the prior art there may befound some N-aryl-N-(4-piperidinyl)amides having pharmacological, e.g.,analgesic, properties. A number of such compounds may be found in thefollowing references:

U.s. pat. No. 2,748,134;

U.s. pat. No. 3,869,463;

U.s. pat. No. 3,164,600;

C.a., 78, 147752r (1973); and

C.a., 77, 34349a (1972).

Among other points of difference the anti-arrhythmic compounds of thisinvention differ from such known compounds by the nature of thearylacetamide group attached to the 4-position of the piperidinenucleus.

DESCRIPTION OF THE PREFERRED EMBODIMENTS

The N-aryl-N-(1-L-4-piperidinyl)arylacetamides with which this inventionis concerned may structurally be represented by the formula: ##STR1##and the pharmaceutically acceptable acid addition salts thereof,wherein: L is a member selected from the group consisting of hydrogen,alkyl having from 1 to 10 carbon atoms, cycloalkyl, cycloalkylloweralkyl and lower alkenyl;

Ar is a member selected from the group consisting of phenyl, mono- anddi-substituted phenyl, pyridinyl and 2-pyrimidinyl, wherein eachsubstituent in said mono- and di-substituted phenyl is independentlyselected from the group consisting of halo and lower alkyl;

Ar¹ is a member selected from the group consisting of phenyl, mono- anddi-substituted phenyl, and thienyl, wherein each substituent in saidmono- and di-substituted phenyl is independently selected from the groupconsisting of halo, lower alkyl, hydroxy and lower alkyloxy; and

X is a member selected from the group consisting of hydrogen, loweralkyloxycarbonyl and lower alkyloxymethyl.

More particularly, the term "alkyl" as used in the definition of L ismeant to include straight and branch chained saturated hydrocarbonradicals having therein from 1 to 10 carbon atoms, such as, for example,methyl, ethyl, 1-methylethyl, propyl, 1-methylpropyl, butyl,2-methylbutyl, 1,1-dimethylethyl, pentyl, hexyl, heptyl, decyl and thelike alkyls; "lower alkyl" as used in the foregoing and in subsequentdefinitions refers to straight and branch chained alkyl radicals havingfrom 1 to about 6 carbon atoms, such as, for example, methyl, ethyl,1-methylethyl, propyl, butyl, pentyl, hexyl and the like; "loweralkenyl" refers to alkenyl radicals having from 3 to about 6 carbonatoms, such as, for example, 2-propenyl, 2-butenyl, 3-butenyl,2-pentenyl and the like; the term "cycloalkyl" refers to cyclichydrocarbon radicals having from 3 to 6 carbon atoms, such as,cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl; and the term "halo"is generic to halogens of atomic weight less than 127, i.e. fluoro,chloro, bromo and iodo.

The compounds of formula (I) wherein L, Ar, Ar¹ and X are asabove-defined provided that when Ar and Ar¹ are each phenyl orsubstituted phenyl and X is hydrogen, then said L is other thancycloalkyl having from 5 to 6 carbon atoms, as well as theirpharmaceutically acceptable acid addition salts, are deemed to be noveland as useful therapeutic agents herein they constitute an importantfeature of this invention.

The subject compounds of formula (I) wherein Ar, Ar¹ and X are aspreviously defined and L is hydrogen, (I-a), may generally be preparedstarting from a piperidine derivative of formula (II), wherein Ar and Xare as previously defined and P is an appropriate protecting group suchas, for example, phenylmethyl, lower alkyloxycarbonyl orphenylmethoxycarbonyl, by first acylating (II) with an appropriatearylacetyl halide of formula (III), preferably the chloride, andthereafter eliminating the protecting group P of the thus obtained (IV)following art-known procedures. ##STR2##

The acylation of (II) with (III) may be carried out following art-knownN-acylating procedures, e.g. by stirring and refluxing the reactantstogether in a suitable reaction-inert organic solvent, preferably in thepresence of an appropriate base. Suitable solvents which may be employedinclude, for example, aromatic hydrocarbons such as, for example,benzene, methylbenzene and dimethylbenzene, and halogenated hydrocarbonssuch as trichloromethane. Appropriate bases include, for example, alkalimetal carbonates and hydrogen carbonates, alkali metal amides such assodium amide, and organic bases such as, for example, pyridine andN,N-diethylethanamine.

The elimination of the protecting group P may be performed according togenerally known methodologies. When the protecting group is phenylmethylor phenylmethoxycarbonyl it is easily removed by catalytic hydrogenationusing an appropriate catalyst, e.g., palladium-on-charcoal, and when theprotecting group is lower alkyloxycarbonyl its elimination may easily beaccomplished by acid or alkaline hydrolysis. Acid hydrolysis may becarried out using a strong mineral acid, e.g., hydrochloric, hydrobromicor sulfuric acid and alkaline hydrolysis is conveniently carried outusing alcoholic alkali, e.g. potassium hydroxide in 2-propanol.

The compounds of formula (I) wherein Ar, Ar¹ and X are as previouslydefined, and L is as previously defined but other than hydrogen, said Lbeing represented by L¹ and said compounds by the formula (I-b), may beprepared by introducing the appropriate L¹ -substituent into anappropriate compound (I-a), according to known N-alkylating procedures.

Conveniently said N-alkylation may be achieved by reacting (I-a) with anappropriate reactive ester of the formula L¹ -Y, (V), wherein L¹ is asdefined hereinabove and Y is an appropriate reactive ester radical suchas, for example, halo, or a sulfonyl radical such as methanesulfonyl or4-methylbenzenesulfonyl. The foregoing reaction may be carried out inthe usual manner, for example, by stirring and refluxing the reactantstogether in an appropriate reaction-inert organic solvent such as, forexample, a lower alkanol, e.g., methanol, ethanol, propanol, butanol andthe like alcohols; an aromatic hydrocarbon, e.g. benzene, methylbenzene,dimethylbenzene, and the like; a ketone, e.g., 4-methyl-2-pentanone; anether, e.g., 1,4-dioxane, 1,1'-oxybisethane and the like;N,N-dimethylformamide; nitrobenzene; and the like. In order to bind theacid which is liberated during the course of the reaction there may beadded an appropriate base such as, for example, sodium or potassiumcarbonate or hydrogen carbonate or an organic base such as, for example,N,N-diethylethanamine. A small amount of an alkali metal iodide, e.g.,potassium iodide, may be added to enhance the reaction rate, especiallywhen the reactive ester (V) is a chloride or bromide.

When L¹ in the compounds (I-b) has the meaning of alkyl, cycloalkyl orcycloalkyl-lower alkyl and when the carbon atom attached to thepiperidine nitrogen has thereon at least one hydrogen atom, theintroduction of said L¹ may equally well be performed by catalytichydrogenation of a mixture of an appropriate aldehyde or ketonecorresponding to the alcohol L¹ -OH, and a compound of formula (I-a) inthe presence of an appropriate catalyst such as, for example,palladium-on-charcoal. In order to improve the selectivity of thehydrogenation reaction there may be added to the mixture a small amountof an appropriate catalyst poison such as, for example, thiophene.

Alternatively the compounds (I-b) may be obtained by the reaction of L¹Y with a phenylmethyl-substituted compound of formula (II-1) to form aquaternary piperidinium salt of formula (VI), and subsequent reductiveelimination of the phenylmethyl group. The quaternization reaction maybe carried out, for example, by heating the reactants together in anappropriate solvent, such as acetonitrile, and elimination of thephenylmethyl group may be performed by catalytic hydrogenation usingpalladium-on-charcoal catalyst. The foregoing reactions are illustratedin the following schematic representation. ##STR3##

Still another method of preparing the compounds of formula (I-b)consists in acylating an appropriate N-aryl-1-L¹ -4-piperidinamine offormula (VII) with an appropriate arylacetyl halide of formula (III)according to well-known N-acylating procedures as described hereinabovefor the preparation of (IV) starting from (II) and (III). ##STR4##

When Ar¹ in the compounds (I-b) has the meaning of a substituted phenylgroup having as substituents one or two hydroxylgroups, alone ortogether with other substituents, it is appropriate to protect saidhydroxylgroups in the corresponding starting materials (III) with anappropriate protecting group such as lower alkyloxycarbonyl, whereupon acorresponding derivative of (I-b) is obtained, the protecting group ofwhich is easily removed by alkaline hydrolysis using for example dilutedaqueous alkali.

The subject compound may be converted to the pharmaceutically acceptableacid addition salt form by treatment with an appropriate acid, such as,for example, an inorganic acid, such as hydrohalic acid, e.g.,hydrochloric, hydrobromic, and the like, and sulfuric acid, nitric acid,phosphoric acid and the like; or an organic acid, such as, for example,acetic, propanoic, 2-hydroxyacetic, 2-hydroxypropanoic, 2-oxopropanoic,propanedioic, butanedioic, (Z)-2-butenedioic, (E)-2-butenedioic,2-hydroxybutanedioic, 2,3-dihydroxybutanedioic,2-hydroxyl-1,2,3-propanetricarboxylic, benzoic, 3-phenyl-2-propenoic,α-hydroxybenzeneacetic, methanesulfonic, ethanesulfonic,benzenesulfonic, 4-methylbenzenesulfonic, cyclohexanesulfamic,2-hydroxybenzoic, 4-amino-2-hydroxybenzoic and the like acids.Conversely, the salt form can be converted by treatment with alkali intothe free base form.

The intermediates used as starting materials in the foregoingpreparations, a number of which are known compounds, may be prepared asfollows.

The intermediates of formula (II) wherein X stands for hydrogen, (II-a),are conveniently obtained as follows. A 4-piperidinone of formula(VIII), having in the 1-position an appropriate protecting group P, issubjected to a condensation reaction with an appropriate arylamine (IX),e.g. by stirring and refluxing the reactants under azeotropic waterremoval in an appropriate organic solvent, preferably an aromatichydrocarbon such as benzene, methylbenzene or dimethylbenzene in thepresence of an appropriate acid such as, for example,4-methylbenzenesulfonic acid, acetic acid, hydrochloric acid and thelike. The resulting Schiff base (X) is then reduced with an appropriatereducing agent such as, for example, sodium borohydride, or by catalytichydrogenation using, for example, platinum oxide catalyst, to obtain thecorresponding N-aryl-4-piperidinamine (II-a).

The foregoing reactions are more clearly illustrated in the followingschematic representation: ##STR5##

Intermediates of formula (VII) wherein X is hydrogen, (VII-a), areconveniently prepared starting from (II-a) by first eliminating theprotecting group P in the usual manner to obtain aN-aryl-4-piperidinamine of formula (XI) and thereafter introducing theL¹ -substituent as described hereinbefore for the preparation of (I-b)starting from (I-a).

When L¹ in the intermediates (VII-a) has the meaning of a methyl group,(VII-a-1), they may directly be obtained by the reduction of anintermediate (II-a) wherein P is a lower alkyloxycarbonyl group,(II-a-2), with an appropriate reducing agent such as, for examplelithium aluminium hydride. The foregoing reactions are illustrated inthe following schematic representation: ##STR6##

Intermediates of formula (II) wherein X stands for loweralkyloxycarbonyl, (II-b), may be prepared as follows.

1-Phenylmethyl-4-piperidinone (XII) is reacted with an appropriatearylamine (IX) and an alkali metal cyanide, for example potassiumcyanide, in an aqueous organic carboxylic acid system, such as aceticacid, or in an aqueous lower alkanol in the presence of an equivalent ofan inorganic acid, such as hydrochloric acid, whereby introduction ofthe nitrile function and of the amine function is effected in the4-position of the piperidine nucleus, yielding an intermediate offormula (XIII).

The nitrile (XIII) is then converted into the amide (XIV) by acidhydrolysis. Advantageously one may use a concentrated strong, aqueous,inorganic acid for this purpose, such as hydrochloric acid, phosphoricacid and, preferably, sulfuric acid. The amide (XIV) is then furtherhydrolyzed to obtain the corresponding carboxylic acid (XV), by theapplication of known amide-to-acid hydrolysis procedures, for example bytreating (XIV) with a diluted strong acid, e.g., hydrochloric orsulfuric acid, or by alkaline hydrolysis using an appropriate base, e.g.sodium or potassium hydroxide. The thus obtained carboxylic acid (XV) isin turn converted into a metal salt thereof, preferably the sodium salt(XVI), by the reaction with alkali, e.g., with sodium hydroxide. Thecarboxylic acid (XV) need not necessarily be isolated or purified, butmay be utilized as a crude mixture in the preparation of (XVI), or thesalt may be obtained directly when alkaline hydrolysis is carried out.

The salt (XVI) is then converted into the desired ester (II-b) wherein Pstands for phenylmethyl (II-b-1) by the reaction with an appropriatehalo-lower alkane (XVII) in an appropriate solvent such as, for example,hexamethylphosphoric triamide.

Alternatively the esters (II-b-1) may be prepared by converting the acid(XV) into an acyl halide (XVIII) in the usual manner, by the treatmentwith an appropriate halogenating agent, e.g. with sulfinyl chloride, andreacting said acyl halide with an appropriate lower alkanol or simply byreacting the acid with an appropriate alcohol in the presence of anacid.

The foregoing reactions are more clearly illustrated in the followingschematic representation: ##STR7##

The intermediates of formula (II-b) wherein P stands for loweralkyloxycarbonyl or phenylmethoxycarbonyl (II-b-2) are easily derivedfrom (II-b-1) by eliminating the protecting phenylmethyl group andthereafter introducing into the thus obtained (XIX) the loweralkyloxycarbonyl or phenylmethoxycarbonyl group according to art-knownprocedures, e.g., by the reaction of (XIX) with an appropriate loweralkyl or phenylmethyl carbonohalidate, or directly by the reaction of(II-b-1) with a lower alkyl or phenylmethyl carbonohalidate whereuponthe phenylmethyl group of (II-b-1) is replaced by the desired loweralkyloxycarbonyl or phenylmethoxycarbonyl group. ##STR8##

Intermediates of formula (VII) wherein X stands for loweralkyloxycarbonyl (VII-b) are conveniently prepared by introducing the L¹-group into an intermediate (XIX) according to the procedures describedhereinbefore.

The intermediates of formulas (II) and (VII) wherein X stands for loweralkyloxymethyl, (II-c) and (VII-c) respectively, may be prepared asfollows.

An appropriate lower alkyl ester of formula (II-b) is reduced with anappropriate reducing agent such as, for example, sodiumdihydro-bis(2-methoxyethoxy)aluminate (Red-Al) in an appropriate organicsolvent such as, for example, benzene, or with lithium borohydride toobtain a 4-piperidinemethanol of formula (XX). Said (XX) is thensubjected to an O-alkylation reaction with an appropriate alkylatingagent. The O-alkylation step may be carried out by the reaction of (XX)with an appropriate halo-lower alkane or di(lower alkyl) sulfate in anappropriate organic solvent such as, for example, benzene,methylbenzene, dimethylbenzene, tetrahydrofuran and the like, in thepresence of an appropriate quaternary ammonium salt such asN,N,N-triethylbenzenemethanaminium chloride, yielding the desiredintermediate (II-c). The intermediates (VII-c) can be prepared by firsteliminating the protecting group of (II-c) and thereafter introducingthe L¹ -substituent into the thus obtained intermediate (XXI) accordingto the procedures described hereinbefore.

Otherwise the intermediates (VII-c) may still be prepared by reducing anappropriate alkyl ester of formula (VII-b) to the corresponding4-piperidinemethanol (XXII) in a similar manner as described hereinabovefor the preparation of (XX) starting from (II-b), and thereaftersubjecting (XXII) to an O-alkylation reaction with an appropriate loweralkyl alkylating agent according to the procedures indicated for thepreparation of (II-c) starting from (XX).

The foregoing procedures are illustrated hereafter. ##STR9##

The compounds of formula (I) and their pharmaceutically acceptable acidaddition salts show excellent antiarrhythmic properties and as such theyare useful in the normalization of irregular cardial rhythms. Theantiarrhythmic effect of the compounds of this invention is clearlyillustrated in the following experiment in dogs. The test is carried outunder neuroleptanalgesia (1 ml per 10 kg bodyweight of fentanyl (0.4mg/ml) and droperidol (20 mg/ml)). About 16 hours after the ligation ofthe anterior descendent branch of the left coronary artery, dogs exhibita multifocal ventricular arrhythmia. The test compounds were givenintraveneously after a control period of 30 minutes, and the followingcriteria were adopted:

0: no effect.

+: decrease of the number of premature beats and increase of the numberof normal beats by at least 30% as compared to the control value.

++: decrease of the number of premature beats and increase of the numberof normal beats by at least 50% as compared to the control value.

+++: normalisation of cardial rhythm or decrease of the number ofpremature beats and increase of the number of normal beats by at least75% as compared to the control value.

The results obtained in this experiment are given in the followingtables. The compounds listed therein are not given for the purpose oflimiting the invention thereto but only to exemplify the usefulantiarrhythmic properties of all the compounds within the scope offormula (I).

                                      Table I                                     __________________________________________________________________________     ##STR10##                                                                                                             Antiarrhythmic effect                                                         in dogs                              L         Ar       Ar.sup.1                                                                              base or salt form                                                                           2.5 mg/kg                                                                           5 mg/kg                        __________________________________________________________________________    CH.sub.3  4-ClC.sub.6 H.sub.4                                                                    C.sub.6 H.sub.5                                                                       base          ++    -                              C.sub.2 H.sub.5                                                                         4-ClC.sub.6 H.sub.4                                                                    C.sub.6 H.sub.5                                                                       HCl           ++    +++                            nC.sub.3 H.sub.7                                                                        4-ClC.sub.6 H.sub.4                                                                    C.sub.6 H.sub.5                                                                       HCl           -     +++                            iC.sub.3 H.sub.7                                                                        4-ClC.sub.6 H.sub.4                                                                    C.sub.6 H.sub.5                                                                       HCl           ++    +++                            nC.sub.4 H.sub.9                                                                        4-ClC.sub.6 H.sub.4                                                                    C.sub.6 H.sub.5                                                                       HCl           ++    ++                              ##STR11##                                                                              4-ClC.sub.6 H.sub.4                                                                    C.sub.6 H.sub.5                                                                       HCl           0     ++                             nC.sub.6 H.sub.13                                                                       4-ClC.sub.6 H.sub.4                                                                    C.sub.6 H.sub.5                                                                       HCl           0     +++                             ##STR12##                                                                              4-ClC.sub.6 H.sub.4                                                                    C.sub.6 H.sub.5                                                                       HCl           ++    +++                             ##STR13##                                                                              4-ClC.sub.6 H.sub.4                                                                    C.sub.6 H.sub.5                                                                       base          +     ++                             iC.sub.3 H.sub.7                                                                        4-FC.sub.6 H.sub.4                                                                     C.sub.6 H.sub.5                                                                       base          +     ++                             iC.sub.3 H.sub.7                                                                        2-ClC.sub.6 H.sub.4                                                                    C.sub.6 H.sub.5                                                                       base          ++    -                              iC.sub.3 H.sub.7                                                                        3-ClC.sub.6 H.sub.4                                                                    C.sub.6 H.sub.5                                                                       HCl           +     ++                             iC.sub.3 H.sub.7                                                                        4-ClC.sub.6 H.sub.4                                                                    4-FC.sub.6 H.sub.4                                                                    HCl           ++    ++                             iC.sub.3 H.sub.7                                                                        4-ClC.sub.6 H.sub.4                                                                    2-ClC.sub.6 H.sub.4                                                                   base          +     +++                            iC.sub.3 H.sub.7                                                                        4-ClC.sub.6 H.sub.4                                                                    3-ClC.sub.6 H.sub.4                                                                   base          ++    +++                            iC.sub.3 H.sub.7                                                                        4-ClC.sub.6 H.sub.4                                                                    4-ClC.sub.6 H.sub.4                                                                   base          +     ++                             iC.sub.3 H.sub.7                                                                        4-ClC.sub.6 H.sub.4                                                                    3,4-(Cl).sub.2C.sub.6 H.sub.3                                                         base          ++    +++                            iC.sub.3 H.sub.7                                                                        4-ClC.sub.6 H.sub.4                                                                    4-BrC.sub.6 H.sub.4                                                                   base          +     ++                             iC.sub.3 H.sub.7                                                                        4-ClC.sub.6 H.sub.4                                                                    3-CH.sub.3C.sub.6 H.sub.4                                                             HCl           +     ++                             iC.sub.3 H.sub.7                                                                        4-ClC.sub.6 H.sub.4                                                                    4-CH.sub.3C.sub.6 H.sub.4                                                             HCl           ++    ++                             iC.sub.3 H.sub.7                                                                        4-ClC.sub.6 H.sub.4                                                                    3-OCH.sub.3C.sub.6 H.sub.4                                                            base          ++    +++                            iC.sub.3 H.sub.7                                                                        2,6-(Cl).sub.2C.sub.6 H.sub.3                                                          4-ClC.sub.6 H.sub.4                                                                   base          ++    -                              iC.sub.3 H.sub.7                                                                        3,4-(Cl).sub.2C.sub.6 H.sub.3                                                          C.sub.6 H.sub.5                                                                       HCl           +     +++                            iC.sub.3 H.sub.7                                                                        3,4-(Cl).sub.2C.sub.6 H.sub.3                                                          4-ClC.sub.6 H.sub.4                                                                   HCl           +     ++                             iC.sub.3 H.sub.7                                                                        4-BrC.sub.6 H.sub.4                                                                    C.sub.6 H.sub.5                                                                       base          ++    ++                             iC.sub.3 H.sub.7                                                                        2,6-(CH.sub.3).sub.2C.sub.6 H.sub.3                                                    C.sub.6 H.sub.5                                                                       HCl           + +   ++                             iC.sub.3 H.sub.7                                                                        2-Cl,6-CH.sub.3C.sub.6 H.sub.3                                                         C.sub.6 H.sub.5                                                                       HCl           ++    -                              iC.sub.3 H.sub.7                                                                        2,6-(CH.sub.3).sub.2C.sub.6 H.sub.3                                                    4-ClC.sub.6 H.sub.4                                                                   HCl           ++    +++                             ##STR14##                                                                              4-ClC.sub.6 H.sub.4                                                                    4-FC.sub.6 H.sub.4                                                                    base          ++    ++                              ##STR15##                                                                              4-ClC.sub.6 H.sub.4                                                                    2-ClC.sub.6 H.sub.4                                                                   base          +     ++                              ##STR16##                                                                              4-ClC.sub.6 H.sub.4                                                                    3-CH.sub.3C.sub.6 H.sub.4                                                             base          +     +++                             ##STR17##                                                                              4-ClC.sub.6 H.sub.4                                                                    4-CH.sub.3C.sub.6 H.sub.4                                                             HCl           ++    ++                              ##STR18##                                                                              4-ClC.sub.6 H.sub.4                                                                    3-OCH.sub.3C.sub.6 H.sub.4                                                            base          ++    -                              C.sub.2 H.sub.5                                                                         4-ClC.sub.6 H.sub.4                                                                    4-FC.sub.6 H.sub.4                                                                    base          +     +++                            C.sub.2 H.sub.5                                                                         4-ClC.sub.6 H.sub.4                                                                    3-CH.sub.3C.sub.6 H.sub.4                                                             base          ++    ++ +                           C.sub.2 H.sub.5                                                                         4-ClC.sub.6 H.sub.4                                                                    4-CH.sub.3C.sub.6 H.sub.4                                                             base          +     ++                             C.sub.2 H.sub.5                                                                         4-ClC.sub.6 H.sub.4                                                                    3-OCH.sub.3C.sub.6 H.sub.4                                                            base          +     +++                            C.sub.2 H.sub.5                                                                         2,6-(CH.sub.3).sub.2C.sub.6 H.sub.3                                                    C.sub.6 H.sub.5                                                                       base          ++    ++                             nC.sub.3 H.sub.7                                                                        2,6-(CH.sub.3).sub.2C.sub.6 H.sub.3                                                    C.sub.6 H.sub.5                                                                       (COOH).sub.2  ++    +++                            iC.sub.3 H.sub.7                                                                        C.sub.6 H.sub.5                                                                        3-CH.sub.3C.sub.6 H.sub.4                                                             HCl           +++   -                               ##STR19##                                                                              C.sub.6 H.sub.5                                                                        C.sub.6 H.sub.5                                                                       base          ++    +++                             ##STR20##                                                                              C.sub.6 H.sub.5                                                                        3-ClC.sub.6 H.sub.4                                                                   base          +++   -                               ##STR21##                                                                              C.sub.6 H.sub.5                                                                        4-ClC.sub.6 H.sub.4                                                                   base          +     +++                             ##STR22##                                                                              C.sub.6 H.sub.5                                                                        3-ClC.sub.6 H.sub.4                                                                   HCl           ++    +++                            C.sub.2 H.sub.5                                                                         4-ClC.sub.6 H.sub.4                                                                     ##STR23##                                                                            HCl           0     ++                             nC.sub.3 H.sub.7                                                                        4-ClC.sub.6 H.sub.4                                                                     ##STR24##                                                                            HCl           +     ++                             CH.sub.2CHCH.sub.2                                                                      4-ClC.sub.6 H.sub.4                                                                     ##STR25##                                                                            HCl           0     ++                             nC.sub.3 H.sub.7                                                                        2,6-(CH.sub.3).sub.2C.sub.6 H.sub.3                                                     ##STR26##                                                                            (COOH).sub.2  ++    ++                             iC.sub.3 H.sub.7                                                                        C.sub.6 H.sub.5                                                                         ##STR27##                                                                            (COOH).sub.2  +     +++                             ##STR28##                                                                              C.sub.6 H.sub.5                                                                         ##STR29##                                                                            base          +++   -                              iC.sub.3 H.sub.7                                                                        4-ClC.sub.6 H.sub.4                                                                     ##STR30##                                                                            HCl           ++    +++                            iC.sub.3 H.sub.7                                                                        2,6-(CH.sub.3).sub.2C.sub.6 H.sub.3                                                     ##STR31##                                                                            HCl           ++    ++                             iC.sub.3 H.sub.7                                                                         ##STR32##                                                                             C.sub.6 H.sub.5                                                                       base          ++    ++                             iC.sub.3 H.sub.7                                                                         ##STR33##                                                                             3-ClC.sub.6 H.sub.4                                                                   base          +++   -                              iC.sub.3 H.sub.7                                                                         ##STR34##                                                                             4-ClC.sub.6 H.sub.4                                                                   base          ++    +++                            iC.sub.3 H.sub.7                                                                         ##STR35##                                                                             3-CH.sub.3C.sub.6 H.sub.4                                                             (COOH).sub.2  +     ++                              ##STR36##                                                                               ##STR37##                                                                             C.sub.6 H.sub.5                                                                       base          +     ++                              ##STR38##                                                                               ##STR39##                                                                             4-ClC.sub.6 H.sub.4                                                                   base          ++    +++                             ##STR40##                                                                               ##STR41##                                                                             3-CH.sub.3C.sub.6 H.sub.4                                                             base          ++    ++                             iC.sub.3 H.sub.7                                                                         ##STR42##                                                                             C.sub.6 H.sub.5                                                                       base          ++    ++                             iC.sub.3 H.sub. 7                                                                        ##STR43##                                                                             3-ClC.sub.6 H.sub.4                                                                   base          ++    ++                             iC.sub.3 H.sub.7                                                                         ##STR44##                                                                             4-ClC.sub.6 H.sub.4                                                                   base          +     ++                             iC.sub.3 H.sub.7                                                                         ##STR45##                                                                             3-CH.sub.3C.sub.6 H.sub.4                                                             base          +     ++                              ##STR46##                                                                               ##STR47##                                                                             3-ClC.sub.6 H.sub.4                                                                   2 HCl. 1/2 H.sub.2 O                                                                        ++    +++                             ##STR48##                                                                               ##STR49##                                                                             4-ClC.sub.6 H.sub.4                                                                   base          +     ++                              ##STR50##                                                                               ##STR51##                                                                             3-CH.sub.3C.sub.6 H.sub.4                                                             HOOCCHCHCOOH  ++    +++                            H         4-ClC.sub.6 H.sub.4                                                                    C.sub.6 H.sub.5                                                                       HCl           -     ++                             H         2-ClC.sub.6 H.sub.4                                                                    C.sub.6 H.sub.5                                                                       base          +     ++                             H         4-ClC.sub.6 H.sub.4                                                                    4-FC.sub.6 H.sub.4                                                                    base          +     ++                             H         4-ClC.sub.6 H.sub.4                                                                    3-(OCH.sub.3)C.sub.6 H.sub.4                                                          base          +     ++(+)                          H         4-ClC.sub.6 H.sub.4                                                                    2-ClC.sub.6 H.sub.4                                                                   base          +     ++(+)                          __________________________________________________________________________

                                      TABLE II                                    __________________________________________________________________________     ##STR52##                                                                                                       Antiarrhythmic effect in dogs              L     X      Ar.sup.1                                                                              Base or Salt form                                                                           2.5 mg/kg                                                                             5 mg/kg                            __________________________________________________________________________     ##STR53##                                                                          COOCH.sub.3                                                                          3-ClC.sub.6 H.sub.4                                                                   base          +       ++                                  ##STR54##                                                                          COOC.sub.2 H.sub.5                                                                   3-ClC.sub.6 H.sub.4                                                                   HOOCCHCHCOOH  +       ++                                  ##STR55##                                                                          COOC.sub.2 H.sub.5                                                                   4-ClC.sub.6 H.sub.4                                                                   HOOCCHCHCOOH  0       ++                                  ##STR56##                                                                          COOC.sub.2 H.sub.5                                                                   3-CH.sub.3C.sub.6 H.sub.4                                                             HOOCCHCHCOOH  ++      +++                                iC.sub.3 H.sub.7                                                                    CH.sub.2OCH.sub.3                                                                    C.sub.6 H.sub.5                                                                       HCl           ++      ++(+)                              __________________________________________________________________________

As a result of the useful anti-arrhythmic properties of the compounds offormula I and the pharmaceutically acceptable acid addition saltsthereof, there is also provided by this invention a method of treatingcardiac arrhythmia which comprises the systemic administration towarm-blooded animals of an effective anti-arrhythmic amount of at leastone compound of the formula (I) or pharmaceutically acceptable acidaddition salt thereof. Although the amount of the anti-arrhythmiccompound to be administered may vary within rather wide limits,depending on the particular circumstances of the case, doses of fromabout 50 mg to about 500 mg, when administered from 1 to 4 times a dayto adult humans, are generally found effective.

It has been found that certain of the compounds of formula I aresurprisingly active upon oral administration, which is a highlydesirable property in view of their ease of administration. Suchcompounds are those wherein X, Ar and Ar¹ are as previously defined andL is an alkyl radical. In view of their potent anti-arrhythmicproperties and their excellent oral activity, the latter compoundsconstitute a preferred genus within the scope of formula (I). Especiallypreferred compounds are those wherein L is a lower alkyl radical havingfrom 1 to 4 carbon atoms, and in particular 1-methylethyl.

In view of their useful anti-arrhythmic activity, the subject compoundsmay be formulated into various pharmaceutical forms for administrationpurposes. To prepare the pharmaceutical compositions of this invention,an effective anti-arrhythmic amount of the particular compound, in baseor acid-addition salt form, as the active ingredient is combined inintimate admixture with a pharmaceutically acceptable carrier, whichcarrier may take a wide variety of forms depending on the form ofpreparation desired for administration. These pharmaceuticalcompositions are desirably in unitary dosage form suitable, preferably,for administration orally, rectally or by parenteral injection. Forexample, in preparing the compositions in oral dosage form, any of theusual pharmaceutical media may be employed, such as, for example, water,glycols, oils, alcohols and the like in the case of oral liquidpreparations such as suspensions, syrups elixirs and solutions; or solidcarriers such as starches, sugars, kaolin, lubricants, binders,disintegrating agents and the like in the case of powders, pills,capsules and tablets. Because of their ease in administration, tabletsand capsules represent the most advantageous oral dosage unit form, inwhich case solid pharmaceutical carriers are obviously employed. Forparenteral compositions, the carrier will usually comprise sterilewater, at least in large part, though other ingredients, for example, toaid solubility, may be included. Injectable solutions, for example maybe prepared in which the carrier comprises saline solution, glucosesolution or a mixture of saline and glucose solution. Injectablesuspensions may also be prepared in which case appropriate liquidcarriers, suspending agents and the like may be employed. Acid additionsalts of (I), due to their increased water solubility over thecorresponding base form, are obviously more suitable in the preparationof aqueous compositions.

It is especially advantageous to formulate the aforementionedpharmaceutical compositions in dosage unit form for ease ofadministration and uniformity of dosage. Dosage unit form as used in thespecification and claims herein refers to physically discrete unitssuitable as unitary dosages, each unit containing a predeterminedquantity of active ingredient calculated to produce the desiredtherapeutic effect in association with the required pharmaceuticalcarrier. Examples of such dosage unit forms are tablets (includingscored or coated tablets), capsules, pills, powder packets, wafers,injectable solutions or suspensions, teaspoonfuls, tablespoonfuls andthe like, and segregated multiples thereof.

The following examples are intended to illustrate and not to limit thescope of the present invention. Unless otherwise stated all partstherein are by weight.

EXAMPLE I

A mixture of 19 parts of 1-(phenylmethyl)-4-piperidinone, 11.8 parts of3-pyridinamine, 120 parts of methylbenzene and a small volume of4-methylbenzenesulfonic acid is stirred and refluxed for 5 hours. (Thereaction vessel is provided with reflux-condensor and water-separator).After the calculated amount of water is separated, the solvent isevaporated. The oily residue is dissolved in 800 parts of2,2'-oxybispropane and evaporated again, yielding 27 parts ofN-[1-(phenylmethyl)-4-piperidinylidene]-3-pyridinamine as a yellow-brownoil.

To a stirred solution of 27 parts ofN-[1-(phenylmethyl)-4-piperidinylidene]-3-pyridinamine in 40 parts ofethanol are added portionwise 3.8 parts of sodium borohydride. After theaddition is complete, the whole is heated to 50° C. The solvent isevaporated. The oily residue is dissolved in 150 parts of hydrochloricacid 1N and filtered. The filtrate is rendered alkaline with ammoniumhydroxide and extracted with methylbenzene. The organic layer is driedover magnesium sulfate, filtered and evaporated. The solid residue iswashed with 2,2'-oxybispropane and dried, yielding 14 parts ofN-[1-(phenylmethyl)-4-piperidinyl]-3-pyridinamine; mp. 131°-133° C.;beige, amorphous powder.

A mixture of 20 parts ofN-[1-(phenylmethyl)-4-piperidinyl]-3-pyridinamine, 160 parts ofmethanol, 30 parts of water and 12 parts of a concentrated hydrochloricacid solution is hydrogenated at normal pressure and at a temperaturebetween 22°-39° C., in the presence of 7 parts of palladium-on-charcoalcatalyst 10%. After the calculated amount of hydrogen is taken up,hydrogenation is stopped. The catalyst is filtered off and the filtrateis evaporated. The oily residue is dissolved in water. This solution isrendered alkaline with ammonium hydroxide, saturated with solidpotassium carbonate and then extracted with methylbenzene. The extractis dried over potassium carbonate and evaporated. The solid residue isrecrystallized from a mixture of 40 parts of benzene and 32 parts of1,1'-oxybisethane, yielding 3 parts of N-(4-piperidinyl)-3-pyridinamine;mp. 127°-129° C.

EXAMPLE II

A mixture of 171.2 parts of ethyl 4-oxo-1-piperidinecarboxylate, 159.5parts of 4-chlorobenzenamine, 1520 parts of anhydrous methylbenzene anda few crystals of 4-methylbenzenesulfonic acid is stirred and refluxedfor 7 hours. (The reaction vessel is provided with a reflux-condensorand water-separator). The methylbenzene is evaporated and the oilyresidue is distilled in vacuo, yielding 192 parts of oily ethyl4-[(4-chlorophenyl)imino]-1-piperidine-carboxylate; bp. 171°-176° C. at0.4 mm. pressure.

EXAMPLE III

By repeating the procedure of Example II and using an equivalent amountof an appropriate arylamine in place of the 4-chlorobenzenamine usedtherein, the following compounds are obtained:

    ______________________________________                                         ##STR57##                                                                    Ar                bp. at indicated pressure                                   ______________________________________                                        2-ClC.sub.6 H.sub.4                                                                             160-165° C/0.5-0.6 mm.                               2,6-(CH.sub.3).sub.2C.sub.6 H.sub.3                                                             142-145° C/0.01 mm.                                  2-Cl,6-CH.sub.3C.sub.6 H.sub.3                                                                  195-200° C/0.2 mm.                                   4-FC.sub.6 H.sub.4                                                                              145-147° C/0.01 mm.                                  3,4-(Cl).sub.2C.sub.6 H.sub.3                                                                   190-200° C/0.02-0.03 mm.                             3-ClC.sub.6 H.sub.4                                                                             165-170° C/0.01-0.02 mm.                             4-BrC.sub.6 H.sub.4                                                                             180-183° C/0.1 mm.                                   2,5-(Cl).sub.2C.sub.6 H.sub.3                                                                      --                                                       2-pyridinyl          --                                                       ______________________________________                                    

EXAMPLE IV

A mixture of 171 parts of ethyl 4-oxo-1-piperidinecarboxylate, 162 partsof 2,6-dichlorobenzenamine, 800 parts of dimethylbenzene and 1 part of4-methylbenzenesulfonic acid is stirred and refluxed withwater-separator. The reaction mixture is evaporated, yielding 250 partsof ethyl 4-[(2,6-dichlorophenyl)imino]-1-piperidinecarboxylate as aresidue.

EXAMPLE V

A mixture of 34 parts of ethyl 4-oxo-1-piperidinecarboxylate, 20 partsof 2-pyrimidinamine, 8 drops of acetic acid and 90 parts ofmethylbenzene is stirred and refluxed for 28 hours with water-separator.The reaction mixture is evaporated, yielding 50 parts of ethyl4-(2-pyrimidinylimino)-1-piperidinecarboxylate as a residue.

EXAMPLE VI

To a warm solution of 192 parts of ethyl4-[(4-chlorophenyl)-imino]-1-piperidinecarboxylatein 560 parts ofmethanol is added portionwise 23.5 parts of sodium borohydride at 50° C.and over a period of one hour. After the addition is complete, themixture is stirred at the same temperature for 2 hours. The methanol isevaporated. The solid residue is heated with ± 600 parts of water andthe product is extracted with benzene. The extract is dried overmagnesium sulfate and evaporated. The oily residue solidifies ontreating with 2,2'-oxybispropane. The solid is filtered off and dried,yielding 122 parts of ethyl4-[(4-chlorophenyl)amino]-1-piperidinecarboxylate; mp. 115°-118° C.

EXAMPLE VII

Following the procedure of Example VI and using an equivalent amount ofan appropriate ethyl 4-arylimino-1-piperidinecarboxylate, the followingcompounds are prepared:

    ______________________________________                                         ##STR58##                                                                    Ar                   mp. / bp.                                                ______________________________________                                        2-ClC.sub.6 H.sub.4                                                                             mp. 89-93° C                                         2-Cl,6-CH.sub.3C.sub.6 H.sub.3                                                                  mp. 99.5° C                                          4-FC.sub.6 H.sub.4                                                                              bp. 140-142° C/0.01 mm.                              3,4-(Cl).sub.2C.sub.6 H.sub.3                                                                   mp. 113.5° C                                         3-ClC.sub.6 H.sub.4                                                                             mp. 72° C                                            4-BrC.sub.6 H.sub.4                                                                             mp. 116.5° C                                         2,5-(Cl).sub.2C.sub.6 H.sub.3                                                                   mp. 107.2-110.3° C                                   2-pyrimidinyl        --                                                       ______________________________________                                    

EXAMPLE VIII

To a stirred and refluxing mixture of 250 parts of ethyl4-[(2,6-dichlorophenyl)imino]-1-piperidinecarboxylate in 160 parts ofmethanol and 160 parts of 2-propanol are added portionwise 30 parts ofsodium borohydride. Upon completion, stirring at reflux temperature iscontinued for one hour. The warm reaction mixture is poured onto waterand the product is extracted with methylbenzene. The extract is driedand evaporated. The residue is crystallized from a mixture of 160 partsof 2,2'-oxybispropane and 160 parts of petroleumether, yielding 96 partsof ethyl 4-[(2,6-dichlorophenyl)-amino]-1-piperidinecarboxylate; mp.107.2°-116.6° C.

EXAMPLE IX

A mixture of 45 parts of ethyl4-[(2,6-dimethylphenyl)-imino]-1-piperidinecarboxylate, 0.3 parts ofplatinum dioxide in 160 parts of methanol is hydrogenated at normalpressure and at a temperature between 24° and 35° C. After thecalculated amount of hydrogen is taken up, hydrogenation is stopped. Thecatalyst is filtered off and the filtrate is evaporated. The oilyresidue is distilled, to yield 30 parts of the oily free base of ethyl4-[(2,6-dimethylphenyl)amino]-1-piperidinecarboxylate; bp. 148°-153° C.at 0.01 mm. pressure. From this distillate, the hydrochloride salt isprepared in the usual manner in 1,1'-oxybisethane. The precipitatedsolid salt is filtered off and dried, yielding 28.5 parts of ethyl4-[(2,6-dimethylphenyl)amino]-1-piperidinecarboxylate hydrochloride; mp.195.5° C.

A mixture of 10 parts of ethyl4-[(2,6-dimethylphenyl)amino]-1-piperidinecarboxylate and 135 parts ofhydrobromic acid solution 48% is stirred at a temperature between 80°and 110° C. until the evolution of gaseous carbon dioxide is ceased(about one hour). The red-coloured reaction mixture is evaporated invacuo. The residue is taken up in 56 parts of methylbenzene and thelatter is evaporated again. Then evaporation is repeated in a mixture of24 parts of 2-propanone and 40 parts of methylbenzene. The resultingsemi-solid residue is triturated in 80 parts of hot 2-propanone and oncooling, the solid product is precipitated. It is filtered off, washedsuccessively with small amounts of absolute ethanol and 2-propanone anddried, yielding 13 parts of N-(2,6-dimethylphenyl)-4-piperidinaminedihydrobromide; mp. +300° C.

EXAMPLE X

To a stirred and cooled (ice-bath) mixture of 165 parts of ethyl4-(2-pyridinylimino)-1-piperidinecarboxylate and 736 parts of methanolare added portionwise 29.5 parts of sodium borohydride (exothermicreaction). Upon completion, stirring is continued for 1h.30 at roomtemperature. The reaction mixture is evaporated. The residue issuspended in 460 parts of water and the suspension is acidified with aconcentrated hydrochloric acid solution. The whole is alkalized withammonium hydroxide and the product is extracted with methylbenzene. Theextract is dried, filtered and evaporated. The residue is converted intothe ethanedioate salt in 2-propanol and 2,2'-oxybispropane. The salt isfiltered off, washed with 2,2'-oxybispropane and dried in vacuo,yielding 38 parts of ethyl 4-(2-pyridinylamino)-1-piperidinecarboxylateethanedioate.

A mixture of 90 parts of ethyl4-(2-pyridinylamino)-1-piperidinecarboxylate, 90 parts of potassiumhydroxide and 720 parts of 2-propanol is stirred and refluxed for 2days. The reaction mixture is evaporated. 1000 Parts of water are addedto the residue and the product is extracted with dichloromethane. Theextract is dried, filtered and evaporated. The residue is crystallizedfrom 2,2'-oxybispropane, yielding 13 parts ofN-(4-piperidinyl)-2-pyridinamine.

EXAMPLE XI

A mixture of 7 parts of ethyl4-(2-pyrimidinylamino)-1-piperidinecarboxylate and 120 parts ofhydrobromic acid solution 48% is stirred and refluxed for 2 hours. Thereaction mixture is evaporated and the residue is taken up in water. Thewhole is alkalized with a diluted sodium hydroxide solution whilecooling in an ice-bath. The product is extracted with dichloromethane.The extract is dried, filtered and evaporated. The solid residue isstirred in 2,2'-oxybispropane. The product is filtered off and convertedinto the hydrochloride salt in 2-propanol. The salt is filtered off andcrystallized from ethanol, yielding 2 parts ofN-(4-piperidinyl)-2-pyrimidinamine dihydrochloride hemihydrate; mp.268.5° C.

EXAMPLE XII

A mixture of 32.5 parts of methyl4-(phenylamino)-1-(phenylmethyl)-4-piperidinecarboxylate and 200 partsof methanol is hydrogenated at normal pressure and at room temperaturewith 5 parts of palladium-on-charcoal catalyst 10%. After the calculatedamount of hydrogen is taken up, the catalyst is filtered off and thefiltrate is evaporated. The oily residue solidifies on scratching in2,2'-oxybispropane. The product is filtered off and dried in vacuo,yielding 20 parts (85%) of methyl4-(phenylamino)-4-piperidinecarboxylate; mp. 139.1° C.

EXAMPLE XIII

To a stirred solution of 58 parts of ethyl4-[(4-chlorophenyl)amino]-1-piperidinecarboxylate in 240 parts ofbenzene is added dropwise a solution of 46.2 parts of benzeneacetylchloride in 80 parts of benzene at a temperature between 40°-70° C. Uponcompletion, the whole is stirred and refluxed for 6h. 15. The reactionmixture is cooled and filtered. The filtrate is washed successively withwater, sodium hydrogen carbonate solution and water, then dried andevaporated in vacuo. The residue is crystallized from 1,1'-oxybisethane,yielding 47 parts of ethyl4-[N-(4-chlorophenyl)-N-(phenylacetyl)amino]-1-piperidinecarboxylate;mp. 108° C.

EXAMPLE XIV

Following the procedure of Example XIII and using equivalent amountsrespectively of an appropriate ethyl 4-arylamino-1-piperidinecarboxylateand of an appropriate arylacetyl chloride in place of the ethyl4-[(4-chlorophenyl)amino]-1-piperidinecarboxylate and benzeneacetylchloride used therein, the following compounds are prepared:

    ______________________________________                                         ##STR59##                                                                    Ar              Ar.sup.1      mp.                                             ______________________________________                                        2,6-(CH.sub.3).sub.2C.sub.6 H.sub.3                                                          2-thienyl       94.5° C                                 4-ClC.sub.6 H.sub.4                                                                          2-thienyl       98.5° C                                 4-ClC.sub.6 H.sub.4                                                                          4-ClC.sub.6 H.sub.4                                                                          127.5° C                                 4-ClC.sub.6 H.sub.4                                                                          4-CH.sub.3C.sub.6 H.sub.4                                                                    112.5° C                                 2-ClC.sub.6 H.sub.4                                                                          C.sub.6 H.sub.5                                                                              123.0° C                                 2-Cl,6-CH.sub.3C.sub.6 H.sub.3                                                               C.sub.6 H.sub.5                                                                              114.5° C                                 4-FC.sub.6 H.sub.4                                                                           C.sub.6 H.sub.5                                                                               82.0° C                                 3,4-(Cl).sub.2C.sub.6 H.sub.3                                                                C.sub.6 H.sub.5                                                                              115.0° C                                 3-ClC.sub.6 H.sub.4                                                                          C.sub.6 H.sub.5                                                                               92.0° C                                 4-ClC.sub.6 H.sub.4                                                                          4-FC.sub. 6 H.sub.4                                                                          109.0° C                                 4-ClC.sub.6 H.sub.4                                                                          3-CH.sub.3C.sub.6 H.sub.4                                                                    121.5° C                                 4-BrC.sub.6 H.sub.4                                                                          C.sub.6 H.sub.5                                                                              114.5°  C                                4-ClC.sub.6 H.sub.4                                                                          3-OCH.sub.3C.sub.6 H.sub.4                                                                   121.2° C                                 4-ClC.sub.6 H.sub.4                                                                          2-ClC.sub.6 H.sub.4                                                                          139.3° C                                 4-ClC.sub.6 H.sub.4                                                                          3-ClC.sub.6 H.sub.4                                                                          142.7° C                                 2-Cl,6-CH.sub.3C.sub.6 H.sub.3                                                               4-ClC.sub.6 H.sub.4                                                                           95.6° C                                 4-ClC.sub.6 H.sub.4                                                                          2,6-(CH.sub.3).sub.2C.sub.6 H.sub.3                                                          120.4° C                                 3,4-(Cl).sub.2C.sub.6 H.sub.3                                                                4-ClC.sub.6 H.sub.4                                                                          136.9° C                                 2,5-(Cl).sub.2C.sub.6 H.sub.3                                                                4-ClC.sub.6 H.sub.4                                                                          107.0° C                                 2,6-(Cl).sub.2C.sub.6 H.sub.3                                                                4-ClC.sub.6 H.sub.4                                                                          140.0° C                                 ______________________________________                                    

example xv

to a stirred solution of 8 parts of ethyl4-[(2,6-dimethylphenyl)amino]-1-piperidinecarboxylate in 4 parts ofpyridine and 80 parts of benzene are added dropwise 7.7 parts ofbenzeneacetyl chloride in 40 parts of benzene. After the addition iscomplete, the whole is heated to reflux and stirred at refluxtemperature for 3h. 45. The reaction mixture is cooled and filtered. Thebenzene-phase is washed with water and then with sodium hydrogencarbonate solution and with water. After evaporation, an oily residue isobtained, which solidifies on triturating in 1,1'-oxybisethane, to yield5 parts of ethyl4-[N-(2,6-dimethylphenyl)-N-(phenylacetyl)amino]-1-piperidinecarboxylate;mp. 106° C.

EXAMPLE XVI

To a stirred solution of 15 parts of ethyl4-[(4-chlorophenyl)-amino]-1-piperidinecarboxylate, 5.4 parts ofN,N-diethylethanamine and 160 parts of benzene is added dropwise 11.07parts of 4-methoxybenzeneacetyl chloride at a temperature between 32° to40° C. After the addition is complete, the whole is stirred and refluxedfor 3 hours. The reaction mixture is cooled and filtered. The filtrateis washed successively with water, sodium hydrogen carbonate solutionand water, dried, filtered and evaporated in vacuo. The oily residue iscrystallized from a mixture of 56 parts of 1,1'-oxybisethane and 40parts of hexane. The crude solid product is filtered off andrecrystallized from a mixture of benzene and 1,1'-oxybisethane, yielding3 parts of ethyl4-{N-(4-chlorophenyl)-N-[(4-methoxyphenyl)acetyl]amino}-1-piperidinecarboxylate;mp. 137° C.

EXAMPLE XVII

A mixture of 20 parts of ethyl4-[N-(2-chlorophenyl)-N-(phenylacetyl)amino]-1-piperidinecarboxylate and300 parts of hydrobromic acid solution 48% is stirred and refluxed for1h. 10. The hydrobromic acid solution 48% is removed in vacuo and to theresidue is added successively water and sodium hydroxide solution. Thefree base is extracted with trichloromethane. The latter is dried andevaporated. The solid residue is washed with 1,1'-oxybisethane anddried, yielding 10.6 parts ofN-(2-chlorophenyl)-N-(4-piperidinyl)benzeneacetamide; mp. 135.5° C.

EXAMPLE XVIII

Following the procedure of Example XVII and using and equivalent amountof an appropriate ethyl4-[N-aryl-N-(arylacetyl)amino]-1-piperidinecarboxylate in place of theethyl4-[N-(2-chlorophenyl)-N-(phenylacetyl)amino]-1-piperidinecarboxylateused therein, the following compounds are obtained:

    ______________________________________                                         ##STR60##                                                                    Ar              Ar.sup.1      mp.                                             ______________________________________                                        2-Cl,6-CH.sub.3C.sub.6 H.sub.3                                                               C.sub.6 H.sub.5                                                                              157° C                                   4-F-C.sub.6 H.sub.4                                                                          C.sub.6 H.sub.5                                                                               96.5° C                                 3,4-(Cl).sub.2C.sub.6 H.sub.3                                                                C.sub.6 H.sub.5                                                                               81° C                                   3-ClC.sub.6 H.sub.4                                                                          C.sub.6 H.sub.5                                                                              110.5° C                                 4-ClC.sub.6 H.sub.4                                                                          4-FC.sub.6 H.sub.4                                                                           109° C                                   4-ClC.sub.6 H.sub.4                                                                          3-CH.sub.3C.sub.6 H.sub.4                                                                    104.5° C                                 4-BrC.sub.6 H.sub.4                                                                          C.sub.6 H.sub.5                                                                              121.5° C                                 4-ClC.sub.6 H.sub.4                                                                          2-ClC.sub.6 H.sub.4                                                                           72.9° C                                 4-ClC.sub.6 H.sub.4                                                                          3-ClC.sub.6 H.sub.4                                                                           64° C                                   2-Cl,6-CH.sub.3C.sub.6 H.sub.3                                                               4-ClC.sub.6 H.sub.4                                                                          120.7° C                                 4-ClC.sub.6 H.sub.4                                                                          2,6-(CH.sub.3).sub.2C.sub.6 H.sub.3                                                          147.3° C                                 3,4-(Cl).sub.2C.sub.6 H.sub.3                                                                4-ClC.sub.6 H.sub.4                                                                           98.7°  C                                2,5-(Cl).sub.2C.sub.6 H.sub.3                                                                4-ClC.sub.6 H.sub.4                                                                          125.6° C                                 2,6-(Cl).sub.2C.sub.6 H.sub.3                                                                4-ClC.sub.6 H.sub.4                                                                          126.3° C                                 ______________________________________                                    

example xix

a mixture of 5 parts of ethyl4-[N-(2,6-dimethylphenyl)-N-(Phenylacetyl)amino]-1-piperidinecarboxylatein 60 parts of hydrobromic acid solution 48% is warmed until theevolution of carbon dioxide is ceased. Heating is continued for 15minutes at a temperature between 80°-120° C. The reaction mixture isevaporated. The solid residue is washed successively with methylbenzeneand 2-propanone and dried, yielding 4.1 parts ofN-(2,6-dimethylphenyl)-N-(4-piperidinyl)benzeneacetamide hydrobromide;mp. 251.5° C.

EXAMPLE XX

A mixture of 10 parts of ethyl4-[N-(4-chlorophenyl)-N-(phenylacetyl)amino]-1-piperidinecarboxylate and125 parts of glacial acetic acid, previously saturated with gaseoushydrogen bromide, is heated for 9h. 45 at 62° C., while stirring. Thereaction mixture is cooled and glacial acetic acid is evaporated invacuo. The semi-solid residue is taken up in 150 parts of water,alkalized with a concentrated sodium hydroxide solution and the productis extracted with trichloromethane. The extract is dried over sodiumsulfate and evaporated. The oily residue is triturated in 56 parts of1,1'-oxybisethane and the solid crude free base is filtered off. It isconverted into the hydrochloride salt in the conventional manner in1,1'-oxybisethane and 2-propanone, yielding 4 parts ofN-(4-chlorophenyl)-N-(4-piperidinyl)benzeneacetamide hydrochloride; mp.206.5° C.

EXAMPLE XXI

Following the procedure of Example XX and using an equivalent amount ofan appropriate ethyl4-[N-aryl-N-(arylacetyl)-amino]-1-piperidinecarboxylate as a startingmaterial, the following compounds are prepared:

N-(2,6-dimethylphenyl)-N-(4-piperidinyl)-2-thiopheneacetamide; mp. 128°C.;

N-(4-chlorophenyl)-N-(4-piperidinyl)-2-thiopheneacetamide hydrochloride;mp. 201.5° C.;

4-chloro-N-(4-chlorophenyl)-N-(4-piperidinyl)-4-benzeneacetamidehydrochloride; mp. 222° C.; and

N-(4-chlorophenyl)-4-methyl-N(4-piperidinyl)benzeneacetamide; mp. 121°C.

EXAMPLE XXII

To a stirred and refluxing mixture of 48 parts of1-(1-methylethyl)-4-piperidinone, 1 part of 4-methylbenzenesulfonic acidand 540 parts of methylbenzene is added dropwise a solution of 30 partsof benzenamine in 90 parts of methylbenzene. Upon completion, the wholeis stirred and refluxed for 3 hours with water-separator. The reactionmixture is evaporated, yielding 72 parts ofN-[1-(1-methylethyl)-4-piperidinylidene]benzenamine as a residue.

To a stirred and warmed (30°-40° C.) solution of 72 parts ofN-[1-(1-methylethyl)-4-piperidinylidene]benzenamine in 480 parts ofmethanol are added portionwise 20 parts of sodium borohydride. Uponcompletion, stirring is continued overnight at at room temperature. Thereaction mixture is evaporated and the residue is dissolved in water.The solution is extracted with 4-methyl-2-pentanone. The extract iswashed with water and acidified with a diluted hydrochloric acidsolution. The aqueous acid phase is alkalized with a diluted sodiumhydroxide solution till pH 9 and the product is extracted with4-methyl-2-pentanone. The extract is washed with water, dried, filteredand evaporated. The residue is distilled (bp. 135°-140° C. at 0.2 mm.pressure) and the distillate is crystallized from petroleumether,yielding 21 parts of 1-(1-methylethyl)-N-phenyl-4-piperidinamine; mp.69.3° C.

EXAMPLE XXIII

To a warm (40° C.) solution of 12 parts of potassium hydroxide in 240parts of 2-propanol are added at once 21 parts of ethyl4-{N-(4-chlorophenyl)-N-[(4-methoxyphenyl)acetyl]amino}-1-piperidinecarboxylateand the whole is stirred and refluxed for 21 hours. The reaction mixtureis cooled, filtered and the filtrate is evaporated. The residue is takenup in water and the aqueous solution is acidified with dilutedhydrochloric acid solution. The acid solution is washed with1,1'-oxybisethane, alkalized with sodium hydroxide and the free base isextracted with methylbenzene. The latter is dried, filtered andevaporated. The residue is dissolved in 1,1'-oxybisethane and aftercrystallization, 10 parts ofN-(4-chlorophenyl)-4-methoxy-N-(4-piperidinyl)benzeneacetamide areobtained; mp. 129.5° C.

EXAMPLE XXIV

To a stirred and warm (40° C.) solution of 12 parts of potassiumhydroxide in 200 parts of 2-propanol are added at once 21 parts of ethyl4-{N-(4-chlorophenyl)-N-[(3-methoxyphenyl)acetyl]-amino}-1-piperidinecarboxylateand the whole is stirred and refluxed for 17 hours. The reaction mixtureis cooled, filtered and evaporated. The semi-solid residue is acidifiedwith a diluted hydrochloric acid solution, washed with 1,1'-oxybisethaneand the aqueous acid phase is alkalized with sodium hydroxide solution.The free base is extracted with trichloromethane. The extract is driedand evaporated. The residue is crystallized from a mixture of1,1'-oxybisethane and hexane, yielding 7.8 parts ofN-(4-chlorophenyl)-3-methoxy-N-(4-piperidinyl)benzeneacetamide; mp.85.7° C.

EXAMPLE XXV

A mixture of 52 parts of 2-bromopropane, 19 parts ofN-(4-piperidinyl)-3-pyridinamine, 33.3 parts of sodium carbonate, 3parts of potassium iodide and 720 parts of 4-methyl-2-pentanone isstirred and refluxed for 24 hours. The reaction mixture is cooled andfiltered. The filtrate is evaporated. The residue is purified bycolumn-chromatography over silica gel using methanol as eluent. The purefractions are collected and the eluent is evaporated. The residue iscrystallized from 2,2'-oxybispropane, yielding 1.5 parts ofN-[1-(1-methylethyl)-4-piperidinyl]-3-pyridinamine; mp. 100.7° C.

EXAMPLE XXVI

Following the procedure of Example XXV and using equivalent amountsrespectively of an appropriate bromide and of an appropriate4-(arylamino)-4-X-piperidine as starting materials and carrying out thereaction in the indicated solvent, the following compounds are obtainedin free base form or in hydrochloride salt form after treatment withhydrochloric acid:

    __________________________________________________________________________     ##STR61##                                                                    L        Ar       X    base or salt form                                                                      mp.  Solvent                                  __________________________________________________________________________    (CH.sub.3).sub.2CH                                                                    C.sub.6 H.sub.5                                                                        COOC.sub.2 H.sub.5                                                                  2 HCl . H.sub.2 O                                                                      148.6° C                                                                    MIK                                      (CH.sub.3).sub.2CH                                                                    C.sub.6 H.sub.5                                                                        COOCH.sub.3                                                                         2 HCl 1/2 H.sub.2 O                                                                    168.7° C                                                                    MIK                                       ##STR62##                                                                            3-pyridinyl                                                                            H     base     134° C                                                                      MIK                                       ##STR63##                                                                            2-pyridinyl                                                                            H     base     143.7° C                                                                    MIK                                       ##STR64##                                                                            C.sub.6 H.sub.5                                                                        COOC.sub.2 H.sub.5                                                                  2 HCl    195.4° C                                                                    MIK                                       ##STR65##                                                                            C.sub.6 H.sub.5                                                                        COOCH.sub.3                                                                         2 HCl    195.4° C                                                                    MIK                                       ##STR66##                                                                            C.sub.6 H.sub.5                                                                        H     2 HCl    --   MIK                                      (CH.sub.3).sub.2CH                                                                    2-pyridinyl                                                                            H     base     93.5° C                                                                     butanol                                  (CH.sub.3).sub.2CH                                                                    2,6-(CH.sub.3).sub.2C.sub.6 H.sub.3                                                    H     base     <50° C                                                                      butanol                                   ##STR67##                                                                            C.sub.6 H.sub.5                                                                        H     2 HCl    259.3° C                                                                    butanol                                  __________________________________________________________________________

EXAMPLE XXVII

To a stirred mixture of 15 parts of N-(4-chlorophenyl)-4-piperidinamine,12 parts of N,N-diethylethanamine in 130 parts of benzene is addeddropwise a solution of 10.3 parts of 3-bromo-1-propene in 70 parts ofbenzene. Upon completion, the whole is stirred first for 20h. 30 at roomtemperature and further for 40 minutes at reflux. The reaction mixtureis cooled, filtered and the filtrate is evaporated. The residue is takenup in 1,1'-oxybisethane and treated with activated charcoal. The latteris filtered off and the 1,1'-oxybisethane is evaporated again, yielding2.9 parts of N-(4-chlorophenyl)-1-(2-propenyl)-4-piperidinamine; mp. 90°C.

EXAMPLE XXVIII

To a warm (about 40° C.) and stirred mixture of 5 parts ofN-(2,6-dimethylphenyl)-4-piperidinamine, 5 parts of sodium carbonate, afew crystals of potassium iodide in 120 parts of benzene is addeddropwise a solution of 5.1 parts of 1-iodopropane in 80 parts ofbenzene. After the addition is complete, stirring is continued for 40hours at reflux temperature. The reaction mixture is cooled and 50 partsof water are added. The organic layer is separated, dried and evaporatedin vacuo. The oily residue is distilled, yielding 10.2 parts ofN-(2,6-dimethylphenyl)-1-propyl-4-piperidinamine; bp. 135° C. at 0.2 mm.pressure.

EXAMPLE XXIX

To 0.5 parts of a solution of 2 parts of thiophene in 40 parts ofethanol, are added 2 parts of cyclopentanone, 5.5 parts ofN-(4-piperidinyl)-2-pyrimidinamine and 120 parts of methanol. The wholeis hydrogenated at normal pressure and at room temperature with 2 partsof palladium-in-charcoal 10%. After the calculated amount of hydrogen istaken up, the catalyst is filtered off and the filtrate is evaporated.The residue is taken up in 4-methyl-2-pentanone and a small amount oftrichloromethane. The whole is washed twice with a diluted sodiumhydroxide solution, dried, filtered and evaporated. The residue iscrystallized from 2,2'-oxybispropane. The product is filtered and dried,yielding 2.3 parts of N-(1-cyclopentyl-4-piperidinyl)-2-pyrimidinamine;mp. 118° C.

EXAMPLE XXX

To 0.5 parts of a solution of 2 parts of thiophene in 40 parts ofethanol, are added 4 parts of 2-propanone, 4.5 parts ofN-(4-piperidinyl)-2-pyrimidinamine and 120 parts of methanol. The wholeis hydrogenated at normal pressure and at room temperature with 2 partsof palladium-on-charcoal catalyst 10%. After the calculated amount ofhydrogen is taken up, the catalyst is filtered off and the filtrate isevaporated. The residue is dissolved in trichloromethane. The solutionis washed successively with a diluted sodium hydroxide solution and withwater, dried, filtered and evaporated, yielding 3 parts ofN-[1-(1-methylethyl)-4-piperidinyl]-2-pyrimidinamine as a residue.

EXAMPLE XXXI

To a stirred and refluxing suspension of 2 parts of lithiumaluminiumhydride in 120 parts of 1,1'-oxybisethane is added dropwise asolution of 13 parts of ethyl4-[N-(2,6-dimethylphenyl)amino]-1-piperidinecarboxylate in 40 parts of1,1'-oxybisethane. After the addition is complete, stirring andrefluxing is continued for 20 hours. The reaction mixture is cooled to5° C. and 7 parts of water are added. The formed precipitate is filteredoff, washed on the filter with 1,1'-oxybisethane and the filtrate isevaporated. The oily residue is distilled, yielding 5.8 parts ofN-(2,6-dimethylphenyl)-1-methyl-4-piperidinamine; bp. 90°-93° C. at0.003 mm. pressure. On standing the distillate solidifies, to yieldsolid N-(2,6-dimethylphenyl)-1-methyl-4-piperidinamine with a meltingpoint of 45° C.

EXAMPLE XXXII

To a stirred suspension of 5 parts ofN-(4-chlorophenyl)-N-(4-piperidinyl)benzeneacetamide, 5 parts of sodiumcarbonate, a few crystals of potassium iodide in 200 parts of butanol isadded dropwise 4 parts of 2-bromopropane at room temperature. After theaddition is complete, the whole is stirred and refluxed for 20 hours.Then the second portion of 4 parts of 2-bromopropane is added andstirring and refluxing is continued for another 19 hours. The reactionmixture is cooled, filtered and the filtrate is evaporated. From theoily free base, the hydrochloride salt is prepared in the conventionalmanner in 1,1'-oxybisethane and 2-propanone. The precipitated solid saltis filtered off and crystallized from a mixture of 2-propanone and2-propanol, yielding 2 parts ofN-(4-chlorophenyl)-N-[1-(1-methylethyl)-4-piperidinyl]benzeneacetamidehydrochloride; mp. 263° C.

EXAMPLE XXXIII

Following the procedure of Example XXXII and using an equivalent amountof an appropriate bromide and of an appropriateN-aryl-N-(4-piperidinyl)arylacetamide as starting materials, thefollowing compounds are prepared in hydrochloride salt form:

    __________________________________________________________________________     ##STR68##                                                                    L                 Ar      Ar.sup.1                                                                              Salt form                                                                           mp.                                   __________________________________________________________________________    (CH.sub.3).sub.2CH                                                                            4-ClC.sub.6 H.sub.4                                                                     2-thienyl                                                                             HCl   273.5° C                       (CH.sub.3).sub.2CH                                                                            2,6-(CH.sub.3).sub.2C.sub.6 H.sub.3                                                     C.sub.6 H.sub.5                                                                       HCl   292° C                         (CH.sub.3).sub.2CH                                                                            2,6-(CH.sub.3).sub.2C.sub.6 H.sub.3                                                     2-thienyl                                                                             HCl   280.5° C                       (CH.sub.3).sub.2CH                                                                            4-ClC.sub.6 H.sub.4                                                                     4-CH.sub.3C.sub.6 H.sub.4                                                             HCl   279° C                         (CH.sub.3).sub.2CH                                                                            2-Cl,6-CH.sub.3C.sub.6 H.sub.3                                                          C.sub.6 H.sub.5                                                                       HCl   266.5° C                       (CH.sub.3).sub.2CH                                                                            4-ClC.sub.6 H.sub.4                                                                     4-OCH.sub.3C.sub.6 H.sub.4                                                            HCl . H.sub.2 O                                                                     264° C                         (CH.sub.3).sub.2CH                                                                            3,4-(Cl).sub.2C.sub.6 H.sub.3                                                           C.sub.6 H.sub.5                                                                       HCl   262.5° C                       (CH.sub.3).sub.2CH                                                                            3-ClC.sub. 6 H.sub.4                                                                    C.sub.6 H.sub.5                                                                       HCl   221.5° C                       (CH.sub.3).sub.2CH                                                                            4-ClC.sub.6 H.sub.4                                                                     4-FC.sub.6 H.sub.4                                                                    HCl   270.5° C                       (CH.sub.3).sub.2CH                                                                            4-ClC.sub.6 H.sub.4                                                                     3-CH.sub.3C.sub.6 H.sub.4                                                             HCl   261.5° C                       (CH.sub.3).sub.2CH                                                                            3,4-(Cl).sub.2C.sub.6 H.sub.3                                                           4-ClC.sub.6 H.sub.4                                                                   HCl   268.6° C                       n-C.sub.4 H.sub.9                                                                             4-ClC.sub.6 H.sub.4                                                                     C.sub.6 H.sub.5                                                                       HCl   224° C                         CH.sub.3CH.sub.2CH(CH.sub.3)                                                                  4-ClC.sub.6 H.sub.4                                                                     C.sub.6 H.sub.5                                                                       HCl   245.5° C                       CH.sub.3CH(CH.sub.3)CH.sub.2CH.sub.2                                                          4-ClC.sub.6 H.sub.4                                                                     C.sub.6 H.sub.5                                                                       HCl   225.5° C                       nC.sub.6 H.sub.13                                                                             4-ClC.sub.6 H.sub.4                                                                     C.sub.6 H.sub.5                                                                       HCl   177.5° C                       nC.sub.7 H.sub.15                                                                             4-ClC.sub.6 H.sub.4                                                                     C.sub.6 H.sub.5                                                                       HCl   157.5° C                       nC.sub.10 H.sub.21                                                                            4-ClC.sub.6 H.sub.4                                                                     C.sub.6 H.sub.5                                                                       HCl   138.5° C                        ##STR69##      4-ClC.sub.6 H.sub.4                                                                     4-CH.sub.3C.sub.6 H.sub.4                                                             HCl   276.8° C                        ##STR70##      4-ClC.sub.6 H.sub.4                                                                     C.sub.6 H.sub.5                                                                       HCl   274° C                         __________________________________________________________________________

example xxxiv

to a stirred and warm (40° C.) mixture of 5 parts ofN-(4-chlorophenyl)-N-(4-piperidinyl)benzeneacetamide, 5 parts of sodiumcarbonate, a few crystals of potassium iodide and 200 parts of n.butanolis added 3.75 parts of bromocyclopentane and the whole is stirred andrefluxed for 21h.30. Then a second portion of 5 parts ofbromocyclopentane is added and stirring at reflux temperature iscontinued for another 30 hours. The reaction mixture is cooled, filteredand the filtrate is evaporated. The oily residue solidifies ontriturating in 1,1'-oxybisethane. The solid product is filtered off andcrystallized from 1,1'-oxybisethane, yielding 1.1 parts ofN-(4-chlorophenyl)-N-(1-cyclopentyl-4-piperidinyl)benzeneacetamide; mp.139.5° C.

EXAMPLE XXXV

Following the procedure of Example XXXIV and using equivalent amountsrespectively of an appropriate bromide and of an appropriateN-aryl-N-(4-piperidinyl)arylacetamide as starting materials, thefollowing compounds are obtained:

    ______________________________________                                         ##STR71##                                                                    L          Ar          Ar.sup.1     mp.                                       ______________________________________                                        (CH.sub.3).sub.2CH                                                                      4-F-C.sub.6 H.sub.4                                                                        C.sub.6 H.sub.5                                                                            108.5° C                           (CH.sub.3).sub.2CH                                                                      4-Cl-C.sub.6 H.sub.4                                                                       4-Cl-C.sub.6 H.sub.4                                                                       106.5° C                           (CH.sub.3).sub.2CH                                                                      4-Br-C.sub.6 H.sub.4                                                                       C.sub.6 H.sub.5                                                                            97° C                              (CH.sub.3).sub.2CH                                                                      4-Cl-C.sub.6 H.sub.4                                                                       2-Cl-C.sub.6 H.sub.4                                                                       143.2° C                           (CH.sub.3).sub.2CH                                                                      4-Cl-C.sub.6 H.sub.4                                                                       3-OCH.sub.3C.sub.6 H.sub.4                                                                 96.4° C                            (CH.sub.3).sub.2CH                                                                      4-Cl-C.sub.6 H.sub.4                                                                       3-Cl-C.sub.6 H.sub.4                                                                       61.6° C                            (CH.sub.3).sub.2CH                                                                      2-Cl,6-CH.sub.3C.sub.6 H.sub.3                                                             4-Cl-C.sub.6 H.sub.4                                                                       94.2° C                            (CH.sub.3).sub.2CH                                                                      4-Cl-C.sub.6 H.sub.4                                                                       2,6-(CH.sub.3).sub.2C.sub.6 H.sub.3                                                        126.6° C                           (CH.sub.3).sub.2CH                                                                      2,5-(Cl).sub.2C.sub.6 H.sub.3                                                              4-Cl-C.sub.6 H.sub.4                                                                       102.5° C                           (CH.sub.3).sub. 2CH                                                                     2,6-(Cl).sub.2C.sub.6 H.sub.3                                                              4-Cl-C.sub.6 H.sub.4                                                                       129.1° C                           (CH.sub.3).sub.2CH                                                                      2-Cl-C.sub.6 H.sub.4                                                                       C.sub.6 H.sub.5                                                                            87.5° C                             ##STR72##                                                                              4-Cl-C.sub.6 H.sub.4                                                                       4-Cl-C.sub.6 H.sub.4                                                                       133.1° C                            ##STR73##                                                                              4-Cl-C.sub.6 H.sub.4                                                                       2-Cl-C.sub.6 H.sub.4                                                                       128.6° C                            ##STR74##                                                                              4-Cl-C.sub.6 H.sub.4                                                                       3-OCH.sub.3C.sub.6 H.sub.4                                                                 157.5° C                            ##STR75##                                                                              4-Cl-C.sub.6 H.sub.4                                                                       3-CH.sub.3C.sub.6 H.sub.4                                                                  155° C                              ##STR76##                                                                              4-Cl-C.sub.6 H.sub.4                                                                       4-F-C.sub.6 H.sub.4                                                                        143.5° C                           ______________________________________                                    

example xxxvi

to a stirred and refluxing mixture of 5 parts ofN-(4-chlorophenyl)-N-(4-piperidinyl)benzeneacetamide, 5 parts of sodiumhydrogen carbonate and 200 parts of benzene are added protionwise 6.7parts of (bromomethyl)cyclopropane and stirring and refluxing iscontinued for 23 hours. The reaction mixture is cooled and filtered. Thefiltrate is evaporated. The semi-solid residue is dissolved in a mixtureof benzene and 1,1'-oxybisethane. The precipitated impurities arefiltered off and the filtrate is evaporated again. From the oily freebase, the hydrochloride salt is prepared in the conventional manner,yielding, after crystallization of the crude salt from a mixture oftrichloromethane and 1,1'-oxybisethane, 1.5 parts ofN-(4-chlorophenyl)-N-[1-(cyclopropylmethyl)-4-piperidinyl]benzeneacetamidehydrochloride; mp. 224° C.

EXAMPLE XXXVII

To a stirred solution of 5 parts ofN-(4-chlorophenyl)-N-(4-piperidinyl)benzeneacetamide, 3.8 parts ofN,N-diethylethanamine in 200 parts of benzene are added portionwise 5parts of 3-bromo-1-propene. After the addition is complete, the whole isheated for 21 hours at a temperature between 50°-60° C. The reactionmixture is cooled and filtered. The filtrate is washed successively withwater, sodium hydrogen carbonate solution and water, dried overpotassium carbonate and evaporated. The oily residue is converted intothe hydrochloride salt in 1,1'-oxybisethane and 2-propanone, yielding 4parts ofN-(4-chlorophenyl)-N-[1-(2-propenyl)-4-piperidinyl]benzeneacetamidehydrochloride; mp. 225.5° C.

EXAMPLE XXXVIII

Following the procedure of Example XXXVII and using an equivalent amountof an appropriate N-aryl-N-(4-piperidinyl)arylacetamide in place of theN-(4-chlorophenyl)-N-(4-piperidinyl)-benzeneacetamide used therein, thefollowing compounds are prepared:

N-(2,6-dimethylphenyl)-N-[1-(2-propenyl)-4-piperidinyl]-2-thiopheneacetamidehydrochloride; mp. 203.5° C.; and

N-(2,6-dimethylphenyl)-N-[1-(2-propenyl)-4-piperidinyl]benzeneacetamidehydrochloride; mp. 214° C.

EXAMPLE XXXIX

To a warm suspension of 5 parts ofN-(4-chlorophenyl)-N-(4-piperidinyl)benzeneacetamide, 5 parts of sodiumcarbonate, a few crystals of potassium iodide in 200 parts of n.butanolis added 4 parts of 2-chloro-2-methylpropane at a temperature of 30°-40°C. The whole is stirred and refluxed for 140 hours during which time, 35parts of 2-chloro-2-methylpropane are added in portions as follows:after a reflux-time of 15 hours, 4 parts of 2-chloro-2-methylpropane isadded, after 8 hours, 10 parts, after 16 hours, 11 parts and finallyafter 47 hours, 10 parts. The reaction mixture is cooled, filtered andthe filtrate is evaporated. The semi-solid residue is dissolved in amixture of methylbenzene, dimethoxyethane and 1,1'-oxybisethane. Thesolution is filtered from some impurities and the filtrate is evaporatedagain. From the oily residue, the hydrochloride salt is prepared in theconventional manner in 1,1'-oxybisethane, yielding, afterrecrystallization of the crude solid salt from 2-propanone, 0.9 parts ofN-(4-chlorophenyl)-N-[1-(1,1-dimethylethyl)-4-piperidinyl]benzeneacetamidehydrochloride; mp. 221° C.

EXAMPLE XL

A mixture of 4 parts of iodoethane, 5 parts ofN-(2,6-dimethylphenyl)-N-(4-piperidinyl)benzeneacetamide, 5 parts ofsodium carbonate, a few crystals of potassium iodide in 200 parts ofbenzene is stirred and refluxed for 23 hours. The reaction mixture isfiltered hot and the filtrate is evaporated in vacuo. The solid residueis crystallized from 1,1'-oxybisethane, yielding 2 parts ofN-(2,6-dimethylphenyl)-N-(1-ethyl-4-piperidinyl)-benzeneacetamide; mp.86.5° C.

EXAMPLE XLI

Following the procedure of Example XL and using an equivalent amount ofan appropriate N-aryl-N-(4-piperidinyl)-arylacetamide in place of theN-(2,6-dimethylphenyl)-N-(4-piperidinyl)benzeneacetamide used therein,the following compounds are prepared:

2-chloro-N-(4-chlorophenyl)-N-(1-ethyl-4-piperidinyl)benzeneacetamidehydrochloride; mp. 234.6° C.;

N-(4-chlorophenyl)-N-(1-ethyl-4-piperidinyl)-3-methylbenzeneacetamide;mp. 78.5° C.;

N-(4-chlorophenyl)-N-(1-ethyl-4-piperidinyl)-4-methylbenzeneacetamide;mp. 50° C.; and

N-(4-chlorophenyl)-N-(1-ethyl-4-piperidinyl)-4-fluorobenzeneacetamide;mp. 62.3° C.

EXAMPLE XLII

To a stirred and refluxing mixture of 5 parts of4-chloro-N-(4-chlorophenyl)-N-(4-piperidinyl)benzeneacetamide, 5 partsof sodium carbonate, 0.4 parts of potassium iodide and 200 parts ofbutanol is added 4.7 parts of 1-iodopropane and the whole is stirred andrefluxed for 22 hours. Then a second portion of 4.5 parts of1-iodopropane is added and stirring and refluxing is continued for27h.30. The reaction mixture is cooled, filtered and the filtrate isevaporated. The semi-solid residue is dissolved in methylbenzene. Thesolution is filtered from some impurities and the filtrate is evaporatedagain. The residue is crystallized from 1,1'-oxybisethane at -10° C.,yielding 0.9 parts of4-chloro-N-(4-chlorophenyl)-N-(1-propyl-4-piperidinyl)benzeneacetamide;mp.118.6° C.

EXAMPLE XLIII

To a stirred solution of 4 parts ofN-(4-chlorophenyl)-N-(4-piperidinyl)benzeneacetamide and 3 parts ofN,N-diethylethanamine in 200 parts of benzene are added portionwise 4parts of 1-iodopropane and the whole is stirred and refluxed for 47hours. Then the second portion of 4 parts of 1-iodopropane is added andstirring and refluxing is continued for another 20h.20. The reactionmixture is cooled and filtered. The filtrate is washed with water, driedand evaporated in vacuo. From the oily free base, the hydrochloride saltis prepared in the conventional manner in 1,1'-oxybisethane. Theprecipitated solid salt is filtered off and dried, yielding 3.5 parts ofN-(4-chlorophenyl)-N-(1-propyl-4-piperidinyl)benzeneacetamidehydrochloride; mp. 233.5° C.

EXAMPLE XLIV

Following the procedure of Example XLIII and using an equivalent amountrespectively of an appropriate iodoalkane and of an appropriateN-aryl-N-(4-piperidinyl)arylacetamide in place of the 1-iodopropane andthe N-(4-chlorophenyl)-N-(4-piperidinyl)benzeneacetamide used therein,the following compounds are obtained:

N-(2,6-dimethylphenyl)-N-(1-ethyl-4-piperidinyl)-2-thiopheneacetamidehydrochloride; mp. 258° C.

N-(4-chlorophenyl)-N-(1-ethyl-4-piperidinyl)-2-thiopheneacetamidehydrochloride; mp. 220.5° C.;

N-(4-chlorophenyl)-N-(1-ethyl-4-piperidinyl)benzeneacetamidehydrochloride; mp. 215° C.;

4-chloro-N-(4-chlorophenyl)-N-(1-ethyl-4-piperidinyl)benzeneacetamidehydrochloride; mp. 224° C.; and

N-(4-chlorophenyl)-N-(1-propyl-4-piperidinyl)-2-thiopheneacetamide; mp.241° C.

EXAMPLE XLV

A mixture of 4.5 parts ofN-(1-cyclopentyl-4-piperidinyl)-2-pyrimidinamine, 3.4 parts of3-methylbenzeneacetyl chloride, 2 parts of sodium carbonate and 180parts of dimethylbenzene is stirred and refluxed for 17 hours. Another 9parts of 3-methylbenzeneacetyl chloride is added dropwise. Uponcompletion, stirring is continued for 67 hours at reflux temperature.The reaction mixture is cooled, water is added and the layers areseparated. The organic phase is extracted with a diluted hydrochloricacid solution. The combined aqueous phases are washed with benzene andalkalized with a diluted sodium hydroxide solution while cooling in anice-bath. The product is extracted twice with trichloromethane. Thecombined extracts are dried, filtered and evaporated. The residue isconverted into the ethanedioate salt in 2-propanol. The salt is filteredoff and crystallized twice: first from ethanol and then from methanol,yielding 1 part ofN-(1-cyclopentyl-4-piperidinyl)-3-methyl-N-(2-pyrimidinyl)benzeneacetamideethanedioate; mp. 204.1° C.

EXAMPLE XLVI

Following the procedure of Example XLV and using equivalent amountsrespectively of an appropriate N-aryl-4-piperidinamine and of anappropriate arylacetyl chloride as starting materials, the followingcompounds are obtained in base form or in the form of an acid additionsalt after treatment with the appropriate acid:

    ______________________________________                                         ##STR77##                                                                                                   base                                           L        Ar         Ar.sup.1   or salt form                                                                          mp.                                    ______________________________________                                         ##STR78##                                                                             3-pyridinyl                                                                              C.sub.6 H.sub.5                                                                          (E)-2- butene- dioate                                                                 219.6° C                         ##STR79##                                                                             3-pyridinyl                                                                              3-CH.sub.3C.sub.6 H.sub.4                                                                (E)-2- butene- dioate                                                                 250.3° C                         ##STR80##                                                                             2-pyridinyl                                                                              3-Cl-C.sub.6 H.sub.4                                                                     (COOH).sub.2                                                                          205.9° C                         ##STR81##                                                                             2-pyridinyl                                                                              3-CH.sub.3C.sub.6 H.sub.4                                                                base    107.8° C                         ##STR82##                                                                             2-pyridinyl                                                                              4-Cl-C.sub.6 H.sub.4                                                                     base    119.2° C                         ##STR83##                                                                             2-pyridinyl                                                                              2-thienyl  base    129.4° C                         ##STR84##                                                                             2-pyridinyl                                                                              C.sub.6 H.sub.5                                                                          base    108.8° C                         ##STR85##                                                                             2-pyrimidinyl                                                                            C.sub.6 H.sub.5                                                                          (COOH).sub.2                                                                          223.5° C                        (CH.sub.3).sub.2 -CH-                                                                  3-pyridinyl                                                                              C.sub.6 H.sub. 5                                                                         base    129.4° C                        (CH.sub.3).sub.2 -CH-                                                                  3-pyridinyl                                                                              3-Cl-C.sub.6 H.sub.4                                                                     base    117.7° C                        (CH.sub.3).sub.2 -CH-                                                                  3-pyridinyl                                                                              4-Cl-C.sub.6 H.sub.4                                                                     base    146.6° C                        (CH.sub.3).sub.2 -CH-                                                                  3-pyridinyl                                                                              2-thienyl  base    126.7° C                        (CH.sub.3).sub.2 -CH-                                                                  3-pyridinyl                                                                              3-CH.sub.3C.sub.6 H.sub.4                                                                base    100° C                          (CH.sub.3).sub.2 -CH-                                                                  2-pyridinyl                                                                              3-Cl-C.sub.6 H.sub.4                                                                     base    102.6° C                        (CH.sub.3).sub.2 -CH-                                                                  2-pyridinyl                                                                              C.sub.6 H.sub.5                                                                          base    72.1° C                         (CH.sub.3).sub.2 -CH-                                                                  2-pyridinyl                                                                              4-Cl-C.sub.6 H.sub.4                                                                     base    83.3° C                         (CH.sub.3).sub.2 -CH-                                                                  2-pyridinyl                                                                              3-CH.sub.3C.sub.6 H.sub.4                                                                (COOH).sub.2                                                                          190.6° C                        (CH.sub.3).sub.2 -CH-                                                                  2-pyridinyl                                                                              2-thienyl  (COOH).sub.2                                                                          196.1° C                        (CH.sub.3).sub.2 -CH-                                                                  2-pyrimidinyl                                                                            4-Cl-C.sub.6 H.sub.4                                                                     (COOH).sub.2                                                                          195.7° C                        ______________________________________                                    

example xlvii

a mixture of 5 parts of methyl1-(1-methylethyl)-4-(phenylamino)-4-piperidinecarboxylate, 24 parts of4-chlorobenzeneacetyl chloride, 4 parts of sodium carbonate and 180parts of dimethylbenzene is stirred and refluxed for 32 hours. Thereaction mixture is cooled, washed with a diluted sodium hydroxidesolution and extracted with a diluted hydrochloric acid solution: threelayers are obtained. The oil and the aqueous phase are combined andalkalized with a diluted sodium hydroxide solution. The product isextracted with 4-methyl-2-pentanone. The extract is washed with water,dried, filtered and evaporated. The residue is converted into theethanedioate salt in 2-propanol. The salt is filtered off andcrystallized from a mixture of 2-propanol and 2,2'-oxybispropane,yielding 5 parts (48%) of methyl4-[N-(4-chlorophenyl)acetyl-N-phenylamino]-1-(1-methylethyl)-4-piperidinecarboxylateethanedioate; mp. 154.2° C.

EXAMPLE XLVIII

Following the procedure of Example XLVII and using equivalent amountsrespectively of an appropriate 4-arylamino-4-piperidinecarboxylate andof an appropriate arylacetyl chloride as starting materials, thefollowing compounds are obtained in free base form or in the form of anacid addition salt after treatment with the appropriate acid:

    ______________________________________                                         ##STR86##                                                                                                 base or                                          L          Ar.sup.1   R      salt form                                                                              mp.                                     ______________________________________                                        (CH.sub.3).sub.2CH                                                                      3-CH.sub. 3C.sub.6 H.sub.4                                                                C.sub.2 H.sub.5                                                                      (COOH).sub.2                                                                           198.4° C                         (CH.sub.3).sub.2CH                                                                      C.sub.6 H.sub.5                                                                           C.sub.2 H.sub.5                                                                      (E)-2-butene-                                                                          168.5° C                                                      dioate                                           (CH.sub.3).sub.2CH                                                                      2-thienyl   C.sub.2 H.sub.5                                                                      (COOH).sub.2                                                                           156.8° C                         (CH.sub.3).sub.2CH                                                                      4-ClC.sub.6 H.sub.4                                                                       C.sub.2 H.sub.5                                                                      HCl      191.5° C                         (CH.sub.3).sub.2CH                                                                      3-CH.sub.3C.sub.6 H.sub.4                                                                 CH.sub.3                                                                             (COOH).sub.2                                                                           170° C                           (CH.sub.3).sub.2CH                                                                      3-ClC.sub.6 H.sub.5                                                                       CH.sub.3                                                                             (COOH).sub.2                                                                           152.2° C                         (CH.sub.3).sub.2CH                                                                      C.sub.6 H.sub.5                                                                           CH.sub.3                                                                             (COOH).sub.2                                                                           165.5° C                         (CH.sub.3).sub.2CH                                                                      2-thienyl   CH.sub.3                                                                             (COOH).sub.2                                                                           173.6° C                          ##STR87##                                                                              4-ClC.sub.6 H.sub.4                                                                       C.sub.2 H.sub.5                                                                      (E)-2-butene- dioate                                                                   195.6° C                          ##STR88##                                                                              C.sub.6 H.sub.5                                                                           C.sub.2 H.sub.5                                                                      (E)-2-butene- dioate                                                                   203.3° C                          ##STR89##                                                                              3-ClC.sub.6 H.sub.4                                                                       C.sub.2 H.sub.5                                                                      (E)-2-butene- dioate                                                                   207.8° C                          ##STR90##                                                                              3-CH.sub.3C.sub.6 H.sub.4                                                                 C.sub.2 H.sub.5                                                                      (E)-2-butene- dioate                                                                   188.1° C                          ##STR91##                                                                              C.sub.6 H.sub.5                                                                           CH.sub.3                                                                             (COOH).sub.2                                                                           197.2° C                          ##STR92##                                                                              2-thienyl   CH.sub.3                                                                             (COOH).sub.2                                                                           166.4° C                          ##STR93##                                                                              3-ClC.sub.6 H.sub.4                                                                       CH.sub.3                                                                             base     94° C                             ##STR94##                                                                              3-CH.sub.3C.sub.6 H.sub.4                                                                 CH.sub.3                                                                             (COOH).sub.2                                                                           189.5° C                         ______________________________________                                    

il

to a stirred mixture of 4.4 parts of1-(1-methylethyl)-N-phenyl-4-piperidinamine, 5.3 parts of sodiumcarbonate and 180 parts of benzene are added dropwise 5 parts ofbenzeneacetyl chloride. Upon completion, stirring is continued overnightat reflux. The reaction mixture is cooled, washed successively withwater, a sodium hydrogen carbonate solution and again with water, dried,filtered and evaporated. The residue is converted into the hydrochloridesalt in 2,2'-oxybispropane and 2-propanol. The formed salt is filteredoff and crystallized from a mixture of 2-propanol and2,2'-oxybispropane, yielding 2.5 parts ofN-[1-(1-methylethyl)-4-piperidinyl]-N-phenylbenzeneacetamidehydrochloride; mp. 184.4° C.

EXAMPLE L

Following the procedure of Example IL and using equivalent amountsrespectively of an appropriate N-aryl-4-piperidinamine and of anappropriate arylacetyl chloride as starting materials, the followingcompounds are obtained in base form or in the form of an acid additionsalt after treatment with the appropriate acid:

    __________________________________________________________________________     ##STR95##                                                                    L         Ar      Ar.sup.1                                                                              base or salt form                                                                       mp.                                       __________________________________________________________________________    (CH.sub.3).sub.2CH                                                                     C.sub.6 H.sub.5                                                                        3-CH.sub.3C.sub.6 H.sub.4                                                             HCl       173.6° C                           (CH.sub.3).sub.2CH                                                                     C.sub.6 H.sub.5                                                                        3-ClC.sub.6 H.sub.4                                                                   HCl       204.8° C                           (CH.sub.3).sub.2CH                                                                     C.sub.6 H.sub.5                                                                        2-thienyl                                                                             (E)-2-butenedioate                                                                      168.1° C                           CH.sub.3 2,6-(CH.sub.3).sub.2C.sub.6 H.sub.3                                                    C.sub.6 H.sub.5                                                                       base      95.5° C                            CH.sub.3 4-ClC.sub.6 H.sub.4                                                                    C.sub.6 H.sub.5                                                                       base      115° C                             C.sub.2 H.sub.5                                                                        4-ClC.sub.6 H.sub.4                                                                    3-OCH.sub.3C.sub.6 H.sub.4                                                            base      90.7° C                            nC.sub.3 H.sub.7                                                                       2,6-(CH.sub.3).sub.2C.sub.6 H.sub.3                                                    2-thienyl                                                                             (COOH).sub.2                                                                            153° C                             nC.sub.3 H.sub.7                                                                       2,6-(CH.sub.3).sub.2C.sub.6 H.sub.3                                                    C.sub.6 H.sub.5                                                                       (COOH).sub.2                                                                            161° C                             CH.sub.2CHCH.sub.2                                                                     4-Cl C.sub.6 H.sub.4                                                                   2-thienyl                                                                             HCl       227.5° C                            ##STR96##                                                                             C.sub.6 H.sub.5                                                                        4-ClC.sub.6 H.sub.4                                                                   base      125.1° C                            ##STR97##                                                                             C.sub.6 H.sub.5                                                                        3-CH.sub.3C.sub.6 H.sub.4                                                             (E)-2-butenedioate                                                                      161.3° C                            ##STR98##                                                                             C.sub.6 H.sub.5                                                                        2-thienyl                                                                             base      119° C                              ##STR99##                                                                             C.sub.6 H.sub.5                                                                        3-ClC.sub.6 H.sub.4                                                                   base      121.8° C                            ##STR100##                                                                            C.sub.6 H.sub.5                                                                        C.sub.6 H.sub.5                                                                       base      139.8° C                            ##STR101##                                                                            3-pyridinyl                                                                            4-ClC.sub.6 H.sub.4                                                                   base      149.9° C                            ##STR102##                                                                            3-pyridinyl                                                                            3-ClC.sub.6 H.sub.4                                                                   2 HCl . 1/2H.sub.2 O                                                                    236.6° C                            ##STR103##                                                                            3-pyridinyl                                                                            2-thienyl                                                                             base      159.8° C                            ##STR104##                                                                            C.sub.6 H.sub.5                                                                        4-ClC.sub.6 H.sub.4                                                                   HCl       265.8° C                            ##STR105##                                                                            C.sub.6 H.sub.5                                                                        3-ClC.sub.6 H.sub.4                                                                   HCl       255.4° C                           __________________________________________________________________________

example li

a suspension of 1.25 parts of sodium amide in 56 parts of benzene isstirred under nitrogen atmosphere and warmed to a temperature of 40° C.Then there is added dropwise a solution of 6 parts ofN-(4-chlorophenyl)-1-(1-methylethyl)-4-piperidinamine in 56 parts ofbenzene. Upon completion, the whole is stirred and refluxed for 16h.45.The mixture is cooled to 25° C. and there is added a mixture of 7.8parts of 3,4-dichlorobenzeneacetyl chloride in 88 parts of benzene.After stirring and refluxing for 2 additional hours, the reactionmixture is cooled and 80 parts of water are added. The whole isacidified with a diluted hydrochloric acid solution. The aqueous acidphase is alkalized with sodium hydroxide solution and the free base isextracted with trichloromethane. The extract is dried, filtered andevaporated. The residue is dissolved in a mixture of 80 parts of1,1'-oxybisethane and 120 parts of hexane. The solution is cooledovernight at -10° C., filtered from some impurities and the filtrate isevaporated again. The residue is dissolved in 120 parts of1,1'-oxybisethane, treated with activated charcoal, filtered andevaporated. The latter residue is crystallized from hexane at -10° C.,yielding 2.2 parts of3,4-dichloro-N-(4-chlorophenyl)-N-[1-(1-methylethyl)-4-piperidinyl]benzeneacetamide;mp. 101.7° C.

EXAMPLE LII

Following the procedure of Example LI and using equivalent amountsrespectively of an appropriate N-aryl-4-piperidinamine and of anappropriate arylacetyl chloride as starting materials, the followingcompounds are obtained in base form or in the form of an acid additionsalt after treatment with the appropriate acid:

4-bromo-N-(4-chlorophenyl)-N-[1-(1-methylethyl)-4-piperidinyl]-benzeneacetamide;mp. 118.1° C.;

4-chloro-N-(2,6-dimethylphenyl)-N-[1-(1-methylethyl)-4-piperidinyl]-benzeneacetamidehydrochloride; mp. 268.2° C.; and

N-(4-chlorophenyl)-4-(1-methylethyl)-N-[1-(1-methylethyl)-4-piperidinyl]benzeneacetamide;mp. 104.9° C.

EXAMPLE LIII

5 Parts of4-chloro-N-(4-chlorophenyl)-N-[1-(1-methylethyl)-4-piperidinyl]benzeneacetamideare dissolved in a mixture of 60 parts of 1,1'-oxybisethane and 16 partsof 2-propanone. The resulting solution is acidified with an excess of2-propanol previously saturated with gaseous hydrogen chloride. Theprecipitated salt is filtered off and dried, yielding 7.5 parts of4-chloro-N-(4-chlorophenyl)-N-[1-(1-methylethyl)-4-piperidinyl]benzeneacetamidehydrochloride; mp. 266.6° C.

EXAMPLE LIV

From 6 parts ofN-[1-(1-methylethyl)-4-piperidinyl]-N-phenyl-2-thiopheneacetamide(E)-2-butanedioate, the free base is liberated in the conventionalmanner with a diluted sodium hydroxide solution. The product isextracted with trichloromethane. The extract is washed with water,dried, filtered and evaporated. The residue is converted into theethanedioate salt in 2-propanol. The salt is filtered off and dried,yielding 3.2 parts ofN-[1-(1-methylethyl)-4-piperidinyl]-N-phenyl-2-thiopheneacetamideethanedioate; m. 167.4° C.

EXAMPLE LV

From an aqueous solution of 2.8 parts ofN-(2,6-dimethylphenyl)-N-(1-propyl-4-piperidinyl)-2-thiopheneacetamidedihydrochloride, the free base is liberated by alkalization with sodiumhydrogen carbonate solution. The free base is extracted with1,1'-oxybisethane. The extract is dried and evaporated. The oily residueis dissolved in 56 parts of hexane and after cooling to -10° C., thesolid free base is precipitated. It is filtered off and dried, yielding1.6 parts ofN-(2,6-dimethylphenyl)-N-(1-propyl-4-piperidinyl)-2-thiopheneacetamide;mp. 62.5° C.

EXAMPLE LVI

From 3.9 parts ofN-(1-cyclopentyl-4-piperidinyl)-3-methyl-N-(3-pyridinyl)benzeneacetamide(E)-2-butenedioate, the free base is liberated in the conventionalmanner with a diluted sodium hydroxide solution. After extraction with2,2'-oxybispropane, the latter is washed with water, dried, filtered andevaporated. The residue is converted into the ethanedioate salt inethanol. The salt is filtered off and crystallized from a mixture ofethanol and 2,2'-oxybispropane, yielding 3 parts ofN-(1-cyclopentyl-4-piperidinyl)-3-methyl-N-(3-pyridinyl)benzeneacetamideethanedioate; mp. 192.6° C.

EXAMPLE LVII

A mixture of 50 parts of4-(phenylamino)-1-(phenylmethyl)-4-piperidinecarboxamide and 600 partsof a concentrated hydrochloric acid solution is refluxed for 16 hours.After cooling the reaction mixture is concentrated under diminishedpressure to a volume of 400 parts, whereupon a precipitate is formed. Itis filtered off, washed with water and 2-propanone and dried, yielding43 parts of 4-(phenylamino)-1-(phenylmethyl)-4-piperidinecarboxylic aciddihydrochloride; mp. 261°-263° C. (dec.).

A mixture of 19 parts of4-(phenylamino)-1-(phenylmethyl)-4-piperidinecarboxylic aciddihydrochloride, 14.4 parts of sulfuric acid and 64 parts of ethanol isstirred and refluxed for 16 hours. The solvent is decanted. The residueis dissolved in water. The aqueous solution is alkalized with ammoniumhydroxide and extracted with a mixture of methylbenzene and2,2'-oxybispropane. The combined organic layers are dried over magnesiumsulfate, filtered and evaporated. The oily residue is dissolved in 200parts of 2,2'-oxybispropane and gaseous hydrogen chloride is introducedinto the solution. The precipitated hydrochloride is filtered off,washed with 2-propanol, filtered off again and dried, yielding 11.5parts of ethyl 4-(phenylamino)-1-(phenylmethyl)-4-piperidinecarboxylatedihydrochloride; mp. 212°-214.4° C.

To a stirred and refluxing solution of 101.4 parts of ethyl4-(phenylamino)-1-(phenylmethyl)-4-piperidinecarboxylate in 640 parts ofdry benzene is added dropwise a solution of 172 parts of a sodiumdihydro-bis(2-methoxyethoxy)aluminate 70% in benzene, in 160 parts ofdry benzene. Upon completion, stirring is continued for 2h.30 at 80° C.The reaction mixture is cooled, poured onto ice-water, alkalized withsodium hydroxide solution and the product is extracted with benzene. Theextract is washed twice with water, dried, filtered and evaporated. Theresidue is converted into the hydrochloride salt in 2-propanol and1,1'-oxybisethane. The salt is filtered off, boiled in 2-propanol andafter cooling, the product is filtered off. It is boiled once more inacetonitrile and the salt is filtered off again after cooling. The freebase is liberated in the conventional manner. After extraction with1,1'-oxybisethane, the latter is washed with water, dried andevaporated, yielding 56.6 parts of4-(phenylamino)-1-(phenylmethyl)-4-piperidinemethanol as an oilyresidue.

To a solution of 32 parts of4-(phenylamino)-1-(phenylmethyl)-4-piperidinemethanol in 90 parts ofbenzene are added 0.2 parts of N,N,N-triethylbenzenemethanaminiumchloride and 150 parts of a sodium hydroxide solution 60%. Afterstirring vigourously, there are added dropwise 10.9 parts ofdimethylsulfate at a temperature below 30° C. Upon completion, stirringis continued at room temperature, first for 2H.30 and further, after theaddition of a second portion of 2.6 parts of dimethyl sulfate, for1h.30. The reaction mixture is cooled in ice-water and 200 parts ofwater are added. The organic phase is separated and the aqueous phase isextracted with benzene. The combined organic phases are washed withwater, dried, filtered and evaporated. The residue is purified bycolumn-chromatography over silica gel using a mixture oftrichloromethane and 3% of methanol, saturated with ammonia, as eluent.The pure fractions are collected and the eluent is evaporated, yielding24.8 parts of4-(methoxymethyl)-N-phenyl-1-(phenylmethyl)-4-piperidinamine as aresidue.

A mixture of 10 parts of4-(methoxymethyl)-N-phenyl-1-(phenylmethyl)-4-piperidinamine and 200parts of acetic acid is hydrogenated at normal pressure and at roomtemperature with 2 parts of palladium-on-charcoal catalyst 10%. Afterthe calculated amount of hydrogen is taken up, the catalyst is filteredoff and the filtrate is evaporated. The oily residue is dissolved inwater, cooled and alkalized with ammonium hydroxide. The product isextracted with trichloromethane. The extract is washed with water,dried, filtered and evaporated. The oily residue is purified bycolumn-chromatography over silica gel using a mixture oftrichloromethane and methanol (90:10 by volume) saturated with gaseousammonia, as eluent. The pure fractions are collected and the eluent isevaporated, yielding 4.5 parts of4-(methoxymethyl)-N-phenyl-4-piperidinamine as an oily residue.

A mixture of 10 parts of 2-bromopropane, 9 parts of4-(methoxymethyl)-N-phenyl-4-piperidinamine, 4.9 parts ofN,N-diethylethanamine and 72 parts of N,N-dimethylacetamide is stirredand refluxed for 10.25 hours. After cooling, the formedN,N-diethylethanamine hydrobromide is filtered off and the filtrate isdiluted with water. The product is extracted with methylbenzene. Theextract is washed thoroughly with water, dried, filtered and evaporated.The residue is purified by column-chromatography over silica gel using amixture of trichloromethane and methanol (90:10) as eluent. The purefractions are collected and the eluent is evaporated, yielding 5.7 parts(42.6%) of 4-(methoxymethyl)-1-(1-methylethyl)-N-phenyl-4-piperidinamineas an oily residue.

To a stirred mixture of 5.5 parts of4-(methoxymethyl)-1-(1-methylethyl)-N-phenyl-4-piperidinamine in 56parts of benzene is added dropwise a solution of 13.8 parts ofbenzeneacetyl chloride in 45 parts of benzene at 26°-32° C. Uponcompletion, stirring is continued first for one hour at 26°-32° C. andfurther for 3.60 hours at 38°-55° C. After cooling, the precipitatedproduct is filtered off and converted into the hydrochloride salt in amixture of 2-propanol and 2-propanone (5:1 by volume). The salt isfiltered off and dissolved in absolute ethanol. After standing for 72hours at room temperature, the precipitated product is filtered off,washed with a small amount of 2-propanone and dried, yielding 1.05 partsofN-[4-(methoxymethyl)-1-(1-methylethyl)-4-piperidinyl]-N-phenylbenzeneacetamidehydrochloride; mp. 249.1° C.

EXAMPLE LVIII

By repeating the procedure of steps 1 through 4 of Example LVII and byusing an equivalent amount of an appropriate di(lower alkyl) sulfate instep 5 thereof the following intermediates are prepared from theappropriate starting materials:

4-(methoxymethyl)-N-(3-methylphenyl)-1-(phenylmethyl)-4-piperidinamine;

4-(methoxymethyl)-N-(4-methylphenyl)-1-phenylmethyl)-4-piperidinamine;

4-(methoxymethyl)-N-(2-methylphenyl)-1-(phenylmethyl)-4-piperidinamine;

N-(4-fluorophenyl)-4-(methoxymethyl)-1-(phenylmethyl)-4-piperidinamine;

4-(ethoxymethyl)-N-phenyl-1-(phenylmethyl)-4-piperidinamine; and

4-(ethoxymethyl)-N-(4-fluorophenyl)-1-(phenylmethyl)-4-piperidinamine.

EXAMPLE LIX

Following the procedure of step 7 of Example LVII and using thereinequivalent amounts of respectively an appropriate N-aryl-4-(loweralkyloxymethyl)-1-(phenylmethyl)-4-piperidinamine and an appropriatearylacetyl chloride as starting materials the following intermediateproducts are prepared:

N-[4-(methoxymethyl)-1-(phenylmethyl)-4-piperidinyl]-N-phenylbenzeneacetamide;

N-[4-(methoxymethyl)-1-(phenylmethyl)-4-piperidinyl]-N-(3-methylphenyl)benzeneacetamide;

N-[4-(methoxymethyl)-1-(phenylmethyl)-4-piperidinyl]-N-(4-methylphenyl)benzeneacetamide;

N-[4-(methoxymethyl)-1-(phenylmethyl)-4-piperidinyl]-N-(2-methylphenyl)benzeneacetamide;

N-(4-fluorophenyl)-N-[4-(methoxymethyl)-1-(phenylmethyl)-4-piperidinyl]benzeneacetamide;

N-[4-(ethoxymethyl)-1-(phenylmethyl)-4-piperidinyl]-N-phenylbenzeneacetamide;

N-[4-(ethoxymethyl)-1-(phenylmethyl)-4-piperidinyl]-N-(4-fluorophenyl)benzeneacetamide;

N-[4-(methoxymethyl)-1-(phenylmethyl)-4-piperidinyl]-N-phenyl-4-methylbenzeneacetamide;

N-[4-(methoxymethyl)-1-(phenylmethyl)-4-piperidinyl]-N-phenyl-4-methoxybenzeneacetamide;and

N-[4-(methoxymethyl)-1-(phenylmethyl)-4-piperidinyl]-N-phenyl-2-thiopheneacetamide.

EXAMPLE LX

Following the procedure of step 5 of Example LVII the followingcompounds are prepared starting from the appropriate phenylmethylsubstituted precursors:

N-[4-(methoxymethyl)-4-piperidinyl]-N-phenylbenzeneacetamide;

N-[4-(methoxymethyl)-4-piperidinyl]-N-(3-methylphenyl)benzeneacetamide;

N-[4-(methoxymethyl)-4-piperidinyl]-N-(4-methylphenyl)benzeneacetamide;

N-[4-(methoxymethyl)-4-piperidinyl]-N-(2-methylphenyl)benzeneacetamide;

N-(4-fluorophenyl)-N-[4-(methoxymethyl)-4-piperidinyl]benzeneacetamide;

N-[4-(ethoxymethyl)-4-piperidinyl]-N-phenylbenzeneacetamide;

N-[4-(ethoxymethyl)-4-piperidinyl]-N-(4-fluorophenyl)benzeneacetamide;

N-[4-(methoxymethyl)-4-piperidinyl]-N-phenyl-4-methylbenzeneacetamide;

N-[4-(methoxymethyl)-4-piperidinyl]-N-phenyl-4-methoxybenzeneacetamide;and

N-[4-(methoxymethyl)-4-piperidinyl]-N-phenyl-2-thiopheneacetamide.

EXAMPLE LXI

To a stirred mixture of 7.5 parts ofN-(4-chlorophenyl)-1-(1-methylethyl)-4-piperidinamine and 80 parts of4-methyl-2-pentanone are added dropwise 9 parts of[4-(2-chloro-2-oxoethyl)-phenyl] ethyl carbonate. Upon completion, thewhole is heated to reflux and stirring is continued for one hour atreflux temperature. After cooling, the precipitated product is filteredoff and stirred for 30 minutes in a mixture of alkaline water andtrichloromethane. The layers are separated. The organic phase is dried,filtered and evaporated. The oily residue is purified bycolumn-chromatography over silica gel using a mixture oftrichloromethane and methanol (90:10 by volume) as eluent. The purefractions are collected and the eluent is evaporated yielding 5.5 partsof{4-[2-{(4-chlorophenyl)-[1-(1-methylethyl)-4-piperidinyl]amino}-2-oxoethyl]phenyl}ethyl carbonate as an oily residue.

A mixture of 5.5 parts of{4-[2-{(4-chlorophenyl)[1-(1-methylethyl)-4-piperidinyl]amino}-2-oxoethyl]phenyl}ethyl carbonate and 50 parts of a sodium hydroxide solution 10% isstirred for 90 minutes at 45° C. The reaction mixture is cooled to roomtemperature and acidified with acetic acid to pH 5.5-6. The product isextracted with trichloromethane. The extract is dried, filtered andevaporated. The oily residue is purified by column-chromatography oversilica gel using a mixture of trichloromethane and methanol (80:20 byvolume) as eluent. The pure fractions are collected and the eluent isevaporated. The oily residue is converted into the hydrochloride salt in4-methyl-2-pentanone. The salt is filtered off and dried in vacuo for 12hours at 60° C., yielding 1.9 parts ofN-(4-chlorophenyl)-4-hydroxy-N-[1-(1-methylethyl)-4-piperidinyl]benzeneacetamidemonohydrochloride; mp. 242.9° C.

We claim:
 1. A chemical compound selected from the group consisting ofan N-aryl-N-(4-piperidinyl)arylacetamide having the formula: ##STR106##and the pharmaceutically acceptable acid addition salts thereof,wherein: L is alkyl having from 1 to 10 carbon atoms;Ar is a memberselected from the group consisting of phenyl, mono- and di-substitutedphenyl, wherein each substituent in said mono- and di-substituted phenylis independently selected from the group consisting of halo and loweralkyl; Ar¹ is a member selected from the group consisting of phenyl,mono- and di-substituted phenyl, wherein each substituent in said mono-and di-substituent phenyl is independently selected from the groupconsisting of halo, lower alkyl, hydroxy and lower alkyloxy; and X ishydrogen.
 2. A chemical compound selected from the group consisting ofN-(4-chlorophenyl)-N-[1-(1-methylethyl)-4-piperidinyl]benzeneacetamideand the pharmaceutically acceptable acid addition salts thereof.
 3. Achemical compound selected from the group consisting ofN-(4-chlorophenyl)-N-(1-ethyl-4-piperidinyl)benzeneacetamide and thepharmaceutically acceptable acid addition salts thereof.
 4. A chemicalcompound selected from the group consisting of anN-aryl-N-(4-piperidinyl)arylacetamide having the formula: ##STR107## andthe pharmaceutically acceptable acid addition salts thereof, wherein: Aris a member selected from the group consisting of phenyl, mono- anddi-substituted phenyl,wherein each substituent in said mono- anddi-substituted phenyl is independently selected from the groupconsisting of halo and lower alkyl; Ar¹ is a member selected from thegroup consisting of phenyl, mono- and di-substituted phenyl, whereineach substituent in said mono- and di-substituted phenyl isindependently selected from the group consisting of halo, lower alkyl,hydroxy and lower alkyloxy; and X is hydrogen.
 5. A chemical compoundselected from the group consisting of anN-aryl-N-(4-piperidinyl)arylacetamide having the formula: ##STR108## andthe pharmaceutically acceptable acid addition salts thereof, wherein: Aris a member selected from the group consisting of phenyl, mono- anddi-substituted phenyl, wherein each substituent in said mono- anddi-substituted phenyl is independently selected from the groupconsisting of halo and lower alkyl;Ar¹ is a member selected from thegroup consisting of phenyl, mono- and di-substituted phenyl, whereineach substituent in said mono- and di-substituted phenyl isindependently selected from the group consisting of halo, lower alkyl,hydroxy and lower alkyloxy; and X is hydrogen.
 6. A pharmaceuticalcomposition comprising an inert carrier material and as an activeingredient an effective anti-arrhythmic amount of a chemical compoundselected from the group consisting of anN-aryl-N-(4-piperidinyl)arylacetamide having the formula: ##STR109## andthe pharmaceutically acceptable acid addition salts thereof, wherein: Lis alkyl having from 1 to 10 carbon atoms;Ar is a member selected fromthe group consisting of phenyl, mono- and di-substituted phenyl, whereineach substituent in said mono- and di-substituted phenyl isindependently selected from the group consisting of halo and loweralkyl; Ar¹ is a member selected from the group consisting of phenyl,mono- and di-substituted phenyl, wherein each substituent in said mono-and di-substituted phenyl is independently selected from the groupconsisting of halo, lower alkyl, hydroxy and lower alkyloxy; and X ishydrogen.
 7. A pharmaceutical composition comprising an inert carriermaterial and as an active ingredient an effective anti-arrhythmic amountof a chemical compound selected from the group consisting ofN-(4-chlorophenyl)-N-[1-(1-methylethyl)-4-piperidinyl]benzeneacetamideand the pharmaceutically acceptable acid addition salts thereof.
 8. Apharmaceutical composition comprising an inert carrier material and asan active ingredient an effective anti-arrhythmic amount of a chemicalcompound selected from the group consisting ofN-(4-chlorophenyl)-N-(1-ethyl-4-piperidinyl)benzeneacetamide and thepharmaceutically acceptable acid addition salts thereof.
 9. Apharmaceutical composition comprising an orally ingestiblepharmaceutical carrier and as an active ingredient an effectiveanti-arrhythmic amount of a chemical compound selected from the groupconsisting of an N-aryl-N-(4-piperidinyl)-arylacetamide having theformula: ##STR110## and the pharmaceutically acceptable acid additionsalts thereof, wherein: Ar is a member selected from the groupconsisting of phenyl, mono- and di-substituted phenyl, wherein eachsubstituent in said mono- and di-substituted phenyl is independentlyselected from the group consisting of halo and lower alkyl;Ar¹ is amember selected from the group consisting of phenyl, mono- anddi-substituted phenyl, wherein each substituent in said mono- anddi-substituted phenyl is independently selected from the groupconsisting of halo, lower alkyl, hydroxy and lower alkyloxy; and X ishydrogen.
 10. A pharmaceutical composition comprising an orallyingestible carrier and as an active ingredient an effectiveanti-arrhythmic amount of a chemical compound selected from the groupconsisting of an N-aryl-N-(4-piperidinyl)-arylacetamide having theformula: ##STR111## and the pharmaceutically acceptable acid additionsalts thereof, wherein: Ar is a member selected from the groupconsisting of phenyl, mono- and di-substituted phenyl, wherein eachsubstituent in said mono- and di-substituted phenyl is independentlyselected from the group consisting of halo and lower alkyl;Ar¹ is amember selected from the group consisting of phenyl, mono- anddi-substituted phenyl, wherein each substituent in said mono- anddi-substituted phenyl is independently selected from the groupconsisting of halo, lower alkyl, hydroxy and lower alkyloxy; and X ishydrogen.
 11. A pharmaceutical composition comprising an orallyingestible carrier and as an active ingredient an effectiveanti-arrhythmic amount of a chemical compound selected from the groupconsisting ofN-(4-chlorophenyl)-N-[1-(1-methylethyl)-4-piperidinyl]benzeneacetamideand the pharmaceutically acceptable acid addition salts thereof.
 12. Apharmaceutical composition comprising an orally ingestible carrier andas an active ingredient an effective anti-arrhythmic amount of achemical compound selected from the group consisting ofN-(4-chlorophenyl)-N-(1-ethyl-4-piperidinyl)benzeneacetamide and thepharmaceutically acceptable acid addition salts thereof.
 13. A method oftreating cardiac arrhythmia which comprises the systemic administrationto warm-blooded animals having said condition of an effectiveanti-arrhythmic amount of a chemical compound selected from the groupconsisting of an N-aryl-N-(4-piperidinyl)arylacetamide having theformula: ##STR112## and the pharmaceutically acceptable acid additionsalts thereof, wherein: L is alkyl having from 1 to 10 carbon atoms;Aris a member selected from the group consisting of phenyl, mono- anddi-substituted phenyl, wherein each substituent in said mono- anddi-substituted phenyl is independently selected from the groupconsisting of halo and lower alkyl; Ar¹ is a member selected from thegroup consisting of phenyl, mono- and di-substituted phenyl, whereineach substituent in said mono- and di-substituted phenyl isindependently selected from the group consisting of halo, lower alkyl,hydroxy and lower alkyloxy; and X is hydrogen.
 14. A method of treatingcardiac arrhythmia which comprises the systemic administration towarm-blooded animals having said condition of an effectiveanti-arrhythmic amount of a chemical compound selected from the groupconsisting ofN-(4-chlorophenyl)-N-[1-(1-methylethyl)-4-piperidinyl]benzeneacetamideand the pharmaceutically acceptable acid addition salts thereof.
 15. Amethod of treating cardiac arrhythmia which comprises the systemicadministration to warm-blooded animals having said condition of aneffective anti-arrhythmic amount of a chemical compound selected fromthe group consisting ofN-(4-chlorophenyl)-N-(1-ethyl-4-piperidinyl)-benzeneacetamide and thepharmaceutically acceptable acid addition salts thereof.